AAO - Cornea - 2011-Consensus and Controversies

Subspecialty Day
2011
Orlando
October 21 22
CORNEA
Cornea 2011:
Controversies and Consensus
Cornea 2011
Controversies and
Consensus
Program Directors
Christopher J Rapuano MD, Natalie A Afshari MD, Anthony J Aldave MD
In conjunction with the Cornea Society

Orange County Convention Center
Orlando, Florida
Saturday, October 22, 2011
Presented by:
The American Academy of Ophthalmology
2011 Cornea Planning Group

Christopher J Rapuano MD
Program Director
Natalie A Afshari MD
Program Director
Anthony J Aldave MD
Program Director
Michael W Belin MD
David B Glasser MD
Donald Tan MD MBBS
Former Program Directors
2010
Michael W Belin MD
David B Glasser MD
2008
2007
Michael W Belin MD
David B Glasser MD
Mark J Mannis MD
Michael W Belin MD
David B Glasser MD
R Doyle Stulting MD PhD
Subspecialty Day Advisory Committee

William F Mieler MD
Associate Secretary
Staff
Melanie R Rafaty CMP, Director,
Scientific Meetings
Ann LEstrange, Scientific Meetings
Coordinator
Debra Rosencrance CMP CAE, Vice
President, Meetings & Exhibits
Patricia Heinicke Jr, Editor
Mark Ong, Designer
Gina Comaduran, Cover Design
Donald L Budenz MD MPH

Daniel S Durrie MD
Robert S Feder MD
Leah Levi MBBS
R Michael Siatkowski MD
Jonathan B Rubenstein MD
Secretary for Annual Meeting
2011 American Academy of Ophthalmology. All rights reserved. No portion may be reproduced without express written consent of the American Academy of Ophthalmology.
ii
2011 Subspecialty Day
Dear Colleague:
On behalf of the American Academy of Ophthalmology and the Cornea Society, it is our great pleasure to welcome you to Orlando and to Cornea 2011: Controversies and Consensus.
As co-chairs of the Cornea Subspecialty Day Program Planning Group, we are honored to plan this
years meeting. We have assembled an outstanding faculty of nationally and internationally recognized experts and anticipate that this will be an extraordinary educational event. Our faculty have
spent innumerable hours preparing their presentations and course materials to provide the most
up-to-date and comprehensive review of their topics. We thank them for all of their efforts and for
sharing their expertise.
The day is divided into six sections. The morning will start off with a discussion of ocular surface
diseases, focusing on replacement versus regeneration. We begin with the most popular keratoprosthesis, the Boston KPro, and proceed to a much less commonly used keratoprosthesis, but one with
a very long track record, the osteo-odonto-keratoprosthesis. Biosynthetic, oral mucosal epithelial,
limbal epithelial and dental pulp cell tranplantation will also be discussed. Session 2 will cover infectious keratitis, including the pros and cons of adjunctive therapy with topical steroids, the use of
collagen crosslinking in infectious keratitis, and an examination of the evidence-based use of perioperative antibiotics. The morning ends with a session on lamellar corneal transplantation, including
tips on transitioning to Descemet-stripping endothelial keratoplasty (DSEK), Descemet membrane
endothelial keratoplasty, and deep anterior lamellar keratoplasty, and for the more experienced
lamellar corneal surgeon, how to achieve success in extreme DSEK.
After lunch, we continue with keratoplasty, focusing on how to choose between penetrating keratoplasty, endothelial keratoplasty, and KPros in the adult population, and then proceed with a discussion on optimizing outcomes in pediatric PK and the utility of KPros as an alternative to PK in the
pediatric population. The next session is on therapeutics: the controversial role of VEGF-inhibitors
in managing corneal neovascularization, uses and abuses of amniotic membrane transplantation,
the role for scleral contact lenses in the management of ocular surface disease, and whats new in the
management of dry eye syndrome. The final session of the day is a potpourri of topics, including the
best uses of corneal topography and other anterior segment imaging techniques, the pros and cons
of using autologous serum, and future therapies for corneal endothelial disease. After each session
there will be a panel discussion to address outstanding issues.
In an effort to provide the most innovative and interesting Subspecialty Day Meetings, we request that
you assist us by completing the evaluation form. We carefully review all comments to better understand your needs, so please candidly indicate the strengths and shortcomings of todays program.
Again, we welcome you to Cornea 2011: Controversies and Consensus. We hope you find it educational and enjoyable.
Sincerely,
Program Director
Program Director
Anthony J Aldave MD
Program Director
Cornea
2011 Subspecialty Day |
Cornea
Cornea 2011 Contents
Program Directors Welcome Letter ii

CME iv
Faculty Listing v
Program Schedule x
Section I:
Ocular Surface DiseaseReplacement vs. Regeneration 1
Section II:
Infectious Keratitis 26
Section III:
Corneal TransplantationLamellar Keratoplasty 35
Section IV:
Corneal TransplantationPenetrating Keratoplasty and Pediatric Keratoplasty 49
Section V:
Ocular Surface DiseaseTherapeutics 58

Surgery by Surgeons Update 64
Section VI:
Cornea Potpourri 65
Faculty Financial Disclosure 81
Presenter Index 85
iii
iv
Cornea
CME Credit
Academys CME Mission Statement

The purpose of the American Academy of Ophthalmologys
Continuing Medical Education (CME) program is to present ophthalmologists with the highest quality lifelong learning
opportunities that promote improvement and change in physician practices, performance or competence, thus enabling such
physicians to maintain or improve the competence and professional performance needed to provide the best possible eye care
for their patients.
2011 Cornea Subspecialty Day Meeting Learning

Objectives
Upon completion of this activity, participants should be able to:
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and outcomes of two types of keratoprostheses for managing advanced ocular surface disease
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of ocular surface cell transplantation
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with the different techniques for corneal replacement (e.g.,
penetrating keratoplasty, Descemet-stripping endothelial
keratoplasty, Descemet membrane endothelial keratoplasty, deep anterior lamellar keratoplasty)
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for pediatric corneal transplantation
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and fungal corneal ulcers
2011 Cornea Subspecialty Day Meeting Target

Audience
The intended audience for this program is cornea surgeons, comprehensive ophthalmologists with an interest in anterior segment
and allied health personnel who are performing or assisting with
cornea surgery.
2011 Cornea Subspecialty Day CME Credit

The American Academy of Ophthalmology is accredited by the
Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The American Academy of Ophthalmology designates this live
activity for a maximum of 7 AMA PRA Category 1 Credits.
Physicians should claim only the credit commensurate with the
extent of their participation in the activity.
Scientific Integrity and Disclosure of Relevant

Financial Interest
The American Academy of Ophthalmology is committed to
ensuring that all continuing medical education (CME) information is based on the application of research findings and the
implementation of evidence-based medicine. It seeks to promote
balance, objectivity and absence of commercial bias in its content. All persons in a position to control the content of this activity must disclose any relevant financial interest. The Academy
has mechanisms in place to resolve all conflicts of interest prior

to an educational activity being delivered to the learners.
Attendance Verification for CME Reporting

Before processing your requests for CME credit, the Academy
must verify your attendance at Subspecialty Day and/or the
Annual Meeting. In order to be verified for CME or auditing
purposes, you must either:
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in the Final Program and/or Subspecialty Day Syllabus
exchange voucher(s) onsite;
r 3FHJTUFSJOBEWBODFBOEQJDLVQZPVSCBEHFPOTJUFJGNBUFrials did not arrive before you traveled to the meeting;
r 3FHJTUFSPOTJUFor
r 6TFZPVS&YQP$BSEBUUIFNFFUJOH
CME Credit Reporting

Level 2, Lobby B; Academy Resource Center, Hall A4,
Booth 1359
Attendees whose attendance has been verified (see above) at the
2011 Annual Meeting can claim their CME credit online during
the meeting. Registrants will receive an e-mail during the meeting
with the link and instructions on how to claim credit.
Onsite, you may report credits earned during Subspecialty Day
and/or the Annual Meeting at the CME Credit Reporting booth.
Academy Members: The CME credit reporting receipt is not
a CME transcript. CME transcripts that include 2011 Annual
Meeting credits entered onsite will be available to Academy
members on the Academys website beginning Nov. 16, 2011.
NOTE: CME credits must be reported by Jan. 18, 2012. After
the 2011 Annual Meeting, credits can be claimed at www.aao.org.
The Academy transcript cannot list individual course attendance. It will list only the overall credits spent in educational
activities at Subspecialty Day and/or the Annual Meeting.
Nonmembers: The Academy will provide nonmembers with
verification of credits earned and reported for a single Academysponsored CME activity, but it does not provide CME credit transcripts. To obtain a printed record of your credits, you must report
your CME credits onsite at the CME Credit Reporting booths.
Proof of Attendance
The following types of attendance verification will be available
during the Annual Meeting and Subspecialty Day for those who
need it for reimbursement or hospital privileges, or for nonmembers who need it to report CME credit:
r $.&DSFEJUSFQPSUJOHQSPPGPGBUUFOEBODFMFUUFST
r 0OTJUF3FHJTUSBUJPO'PSN
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Visit the Academys website for detailed CME reporting
information.
Cornea
Faculty
No photo
available
Penny A Asbell MD FACS
Stuart I Brown MD
Durham, NC
Associate Professor of Ophthalmology
and Director of Cornea and
Refractive Surgery Fellowship
Duke University Eye Center
New York, NY
Professor of Ophthalmology
Mount Sinai School of Medicine
La Jolla, CA
No photo
available
Alan N Carlson MD
Dimitri T Azar MD
Anthony J Aldave MD
Los Angeles, CA
The Jules Stein Eye Institute
Chicago, IL
Interim Dean
College of Medicine
Professor, Field Chair, and Head
Department of Ophthalmology and
Visual Sciences
University of Illinois at Chicago
Durham, NC
Duke Eye Center
James Chodosh MD MPH

Boston, MA
Massachusetts Eye and Ear Infirmary
Harvard Medical School
James V Aquavella MD
Rochester, NY
Flaum Eye Institute
University of Rochester
Keith Hugh Baratz MD

Rochester, MN
Mayo Clinic
vi
Faculty Listing
Cornea
Roy S Chuck MD PhD
Per Fagerholm MD
Jose Gomes MD
Bronx, NY
Professor and Chairman of
Ophthalmology
Albert Einstein College of Medicine
Ophthalmology
Montefiore Medical Center
Stockholm, Sweden
University of Linkping
Sao Paulo, SP, Brazil

Federal University of Sao Paulo
Director of the Cornea and External
Disease Service
Federal University of Sao Paulo
Marjan Farid MD
Reza Dana MD MSc MPH

Boston, MA
Professor and Director of Cornea &
Refractive Surgery
Massachusetts Eye and Ear Infirmary
Department of Ophthalmology
Harvard Medical School
Senior Scientist and W Clement Stone
Scholar
Schepens Eye Research Institute
Huntington Beach, CA
Assistant Professor of Ophthalmology
University of California, Irvine
Director of Cornea, Cataract, and
Refractive Surgery
Gavin Herbert Eye Institute
Kristin M Hammersmith MD
Philadelphia, PA
Andrew J W Huang MD MPH

Kenneth M Goins MD
Iowa City, IA
Professor, Clinical Ophthalmology
University of Iowa
Randy J Epstein MD
Highland Park, IL
Rush University Medical Center
St Louis, MO
Washington University School of
Medicine in St Louis
Faculty Listing
Cornea
Bennie H Jeng MD
Anna S Kitzmann MD
Christopher Liu FRCOphth
San Francisco, CA
University of California, San Francisco
Iowa City, IA
University of Iowa
Brighton, England
Ophthalmology
Sussex Eye Hospital, Brighton
Ophthalmology
Tongdean Eye Clinic (Hove, England)
A John Kanellopoulos MD
Friedrich E Kruse MD
Athens, Greece
New York University Medical College
Erlangen, Germany
University of Erlangen
No photo
available
Shigeru Kinoshita MD
Thomas M Lietman MD
Kyoto, Japan
Kyoto Prefectural University of Medicine
San Francisco, CA
vii
Francis S Mah MD
Sewickley, PA
and Pathology
University of Pittsburgh School of
Medicine
Medical Director
Charles T Campbell Ocular
Microbiology Laboratory
Todd P Margolis MD PhD

San Francisco, CA
Professor of Ophthalmology and
Director, F I Proctor Foundation
University of California, San Francisco
viii
Faculty Listing
Stephanie Jones Marioneaux MD
Rudy Nuijts MD
Chesapeake, VA
American Academy of Ophthalmology
Eastern Medical of Virginia
Maastricht, Limburg, Netherlands

Department of Ophthalmology
Academic Hospital Maastricht
Philadelphia, PA
Chief, Cornea Service
Wills Eye Institute
Jefferson Medical College
Thomas Jefferson University
Cornea
No photo
available
Majid Moshirfar MD
N Venkatesh Prajna MD
Salt Lake City, UT
Tamilnadu, India
Aravind Eye Hospital
George O D Rosenwasser MD
Hershey, PA
Director, Central Pennsylvania Eye
Institute
Medical Director, Gift of Life Donor
Program Eye Bank
Kohji Nishida MD
Osaka, Japan
Ophthalmology
Osaka University Graduate School of
Medicine
Francis W Price Jr MD
Indianapolis, IN
Medical Director
Price Vision Group
President of the Board
Cornea Research Foundation of America
Virender S Sangwan MBBS

Hyderabad, Andhra Pradesh, India
Ophthalmologist
L V Prasad Eye Institute
Faculty Listing
Cornea
Geoffrey C Tabin MD
Mark A Terry MD
Salt Lake City, UT

Professor of Ophthalmology and Visual
Science and Director, International
Division
The John A Moran Center
University of Utah
Codirector, Himalayan Cataract Project
Portland, OR
Director, Corneal Services
Devers Eye Institute
Professor, Clinical Ophthalmology
Oregon Health Sciences University
ix
Cornea
Cornea 2011: Controversies and Consensus

In Conjunction With The Cornea Society
SATURDAY, OCTOBER 22, 2011

6:30 AM
REGISTRATION/ MATERIAL PICKUP/ CONTINENTAL BREAKFAST
8:00 AM
Welcome and Introductions
Section I:
Ocular Surface DiseaseReplacement vs. Regeneration
Christopher J Rapuano MD*

Anthony J Aldave MD*
Natalie A Afshari MD*
Moderator: Anthony J Aldave MD*

Panelists: James Chodosh MD MPH*, Per Fagerholm MD, Jose Gomes MD*, Christopher Liu FRCOphth,
Kohji Nishida MD, Virender S Sangwan MBBS
8:05 AM
The Boston Keratoprosthesis in the Management of Limbal Stem Cell

Failure
James Chodosh MD MPH*
The Osteo-Odonto-Keratoprosthesis for Management of Severe Ocular

Surface Disease
8:25 AM
A Biosynthetic Alternative to Human Donor Tissue
Per Fagerholm MD
18
8:35 AM
Oral Mucosal Epithelial Transplantation for the Management of Ocular

Surface Disease
Kohji Nishida MD
20
8:45 AM
Cultivated Limbal Epithelial Transplantation for the Management of

Ocular Surface Disease
21
8:55 AM
Ocular Surface Reconstruction With Immature Dental Pulp Stem Cell

Transplantation
Jose Gomes MD*
24
8:15 AM
9:05 AM
Panel
Section II:
Infectious Keratitis
Moderator: Natalie A Afshari MD*
Panelists: A John Kanellopoulos MD*, Thomas M Lietman MD, Francis S Mah MD*,
Todd P Margolis MD PhD, N Venkatesh Prajna MD*
9:20 AM
Bacterial Keratitis: Synergy, Steroids, and Other Treatment Controversies
Thomas M Lietman MD
26
9:30 AM
An Evidence-Based Approach to Managing Fungal Keratitis
N Venkatesh Prajna MD*
28
9:40 AM
Corneal Collagen Crosslinking: Does It Have a Role in Managing

Infectious Keratitis?
A John Kanellopoulos MD*
30
Now That We Have Topical Ganciclovir, What Is the Role of

Oral Antivirals?
33
10:00 AM
Perioperative Antibiotics: Looking for a Consensus Amid the Chaos
Francis S Mah MD*
34
10:10 AM
Panel
10:25 AM
REFRESHMENT BREAK and ANNUAL MEETING EXHIBITS
9:50 AM
* Indicates that the presenter has financial interest.

No asterisk indicates that the presenter has no financial interest.
Section III:
Cornea
Program Schedule
xi
Corneal TransplantationLamellar Keratoplasty

Moderator: Christopher J Rapuano MD*
Panelists: Marjan Farid MD, Friedrich E Kruse MD*, Rudy Nuijts MD*, Francis W Price Jr MD*,
George O D Rosenwasser MD*, Geoffrey C Tabin MD, Mark A Terry MD*
10:55 AM
A Decade of Endothelial Keratoplasty: What Has the Literature Taught Us?
Mark A Terry MD*
35
11:05 AM
Ten Tips to Avoid Trouble When Transitioning to Descemet-Stripping

Endothelial Keratoplasty
Friedrich E Kruse MD*
38
Extreme Descemet-Stripping Endothelial Keratoplasty: When You Think

DSEK Is the Best Option for the Cornea, but Not for Your Coronaries
George O D Rosenwasser MD* 41
Descemet Membrane Endothelial Keratoplasty: Is It Time for You to

Convert From Descemet- Stripping Endothelial Keratoplasty?
Francis W Price Jr MD*
11:15 AM
11:25 AM
42
11:35 AM
Deep Anterior Lamellar Keratoplasty: Is It Time for You to Convert

From PK?
Rudy Nuijts MD*
44
11:45 AM
Deep Anterior Lamellar Keratoplasty: Tips for the Transitioning Surgeon
Geoffrey C Tabin MD
46
11:55 AM
Deep Anterior Lamellar Keratoplasty: Why You Should Be Performing It

With a Femtosecond Laser
Marjan Farid MD
47
12:05 PM
Panel
12:20 PM
LUNCH and ANNUAL MEETING EXHIBITS
Section IV:
Corneal TransplantationPenetrating Keratoplasty and Pediatric Keratoplasty

Moderator: Anthony J Aldave MD*
Panelists: James V Aquavella MD*, Stuart I Brown MD, Alan N Carlson MD*, Kenneth M Goins MD,
1:30 PM
1:40 PM
1:50 PM
PK: When I Choose PK Instead of Descemet-Stripping Endothelial

Keratoplasty
Kenneth M Goins MD
49
Failed PK: How I Choose Between Repeat PK and Descemet-Stripping

Alan N Carlson MD*
51
Failed PK: How I Choose Between Repeat PK and a Keratoprosthesis
53
2:00 PM
Transplantation of Congenitally Opaque Corneas: Pearls and Pitfalls
Stuart I Brown MD
55
2:10 PM
Pediatric Keratoprosthesis: Are We There Yet?
James V Aquavella MD*
56
2:20 PM
Panel
Section V:
Ocular Surface DiseaseTherapeutics

Moderator: Natalie A Afshari MD*
Panelists: Penny A Asbell MD FACS*, Roy S Chuck MD PhD*, Reza Dana MD MSc MPH*,
Andrew J W Huang MD MPH*
2:35 PM
What to Do for Corneal Neovascularization
Reza Dana MD MSc MPH*
58
2:45 PM
Amniotic Membrane Grafts: Uses and Controversial Uses
Roy S Chuck MD PhD*
60
2:55 PM
Scleral Contact Lens: Resolving Ocular Surface Issues?
Andrew J W Huang MD MPH* 61

Penny A Asbell MD FACS*
3:05 PM
Dry Eye: A Burning Issue Revisited
3:15 PM
Panel
3:30 PM
REFRESHMENT BREAK and ANNUAL MEETING EXHIBITS

63
xii
Program Schedule
Section VI:
| Cornea
Cornea Potpourri
Moderator: Christopher J Rapuano MD*
Panelists: Dimitri T Azar MD*, Keith Hugh Baratz MD*, Randy J Epstein MD*, Bennie H Jeng MD*,
Shigeru Kinoshita MD*, Anna S Kitzmann MD, Majid Moshirfar MD
4:00 PM
Surgery by Surgeons
Stephanie Jones Marioneaux

MD
64
4:05 PM
Straighten Up and Listen: Ergonomics for Your Aching Back
Anna S Kitzmann MD
65
4:15 PM
Corneal Imaging: Confocal, OCT, and Ultrasound Biomicroscopy

What Are They Good For?
Majid Moshirfar MD
66
Corneal Topography and Tomography Interpretation for the Cataract

SurgeonImplications for Premium and Toric IOLs
Randy J Epstein MD*
69
4:35 PM
Autologous Serum: Is It Worth the Hassle?
Bennie H Jeng MD*
71
4:45 PM
What Is New in the Genetics of Fuchs Dystrophy?
Keith Hugh Baratz MD*
74
4:25 PM
4:55 PM
Future Therapies for Corneal Endothelial Disease
Shigeru Kinoshita MD*
77
5:05 PM
How the Cornea Remains Clear in Health and Disease
Dimitri T Azar MD*
79
5:15 PM
Panel
5:30 PM
Closing Remarks

Christopher J Rapuano MD*

Anthony J Aldave MD*
Natalie A Afshari MD*
Cornea
Section I: Ocular Surface Disease Replacement vs. Regeneration
The Boston Keratoprosthesis in the Management of

Limbal Stem Cell Failure
I. History of the Boston Keratoprosthesis
A. The predicted survival of a corneal allograft (retention of corneal clarity) performed for routine
indications is approximately 50% at 15 years after
surgery, but essentially zero at 5 years after a third
keratoplasty. The Boston Keratoprosthesis has
become a widely utilized option for patients with
corneal allograft failure, and it is the now most
utilized keratoprosthesis in the United States, the
Americas, and Western Europe, with over 1200
devices placed annually worldwide. The Boston
Keratoprosthesis is one of many similar throughand-through collar-button designs; the current Boston design is the product of many years of dedicated
work by Claes H Dohlman MD PhD.
B. FDA approved for marketing in 1992
C. Continual improvement and innovation since inception
1. Contact lens to improve hydration of corneal tissue adjacent to keratoprosthesis stem; prevents
dellen formation at edge of frontplate
2. Holes in backplate allow aqueous contact with
posterior cornea and appear to reduce tissue
necrosis
3. Postoperative topical vancomycin (14 mg/ml
with BAK): In a retrospective study, topical
vancomycin reduced rate of postoperative endophthalmitis due to Gram-positive bacteria to
nearly zero.
II. Design Types of Boston Keratoprosthesis
A. Type I
1. Implanted in corneal donor graft tissue or in
patients own cornea (autograft)
2. Used for patients with normal or near normal
tear film and eyelid anatomy and function
B. Type II
1. Similar to Type I, but with extra stem/optic anterior to corneal plane to extend between/through
surgically closed eyelids
2. Used in patients with end-stage cicatricial ocular
surface disease, severe aqueous tear deficiency,
and/or ocular surface keratinization
III. General Indications for Implantation of a Boston Keratoprosthesis
A. Any patient with corneal blindness not amenable to
corneal allograft surgery
1. Failed corneal graft when a subsequent corneal
allograft is also expected to fail, as in repeated
corneal allograft rejection (Boston Keratoprosthesis Type I)

2. Deep and extensive corneal neovascularization
(Type I)
3. Aniridia (Type I)
4. Stevens Johnson syndrome/ toxic epidermal
necrolysis (Type I or II, depending on severity of
ocular surface disease)
5. Mucous membrane pemphigoid (Type I or II,
depending on severity of ocular surface disease)
6. Post-chemical burn (Type I or II, depending on
severity of ocular surface disease)
7. Other autoimmune conditions (Type I or II,
depending on severity of ocular surface disease)
8. Severe tear film deficiency (Type II)
B. Pediatric patients with poor prognosis for conventional allograft (Type I): Still controversial, but
avoids astigmatism of allograft and allows immediate amblyopia therapy
1. Bilateral Peters anomaly
2. Other congenital or acquired corneal disorders
of infancy
IV. Limbal Stem Cell Failure and the Boston Keratoprosthesis
A. Status of the ocular surface determines choice of
Boston keratoprosthesis type.
Patients with severe tear deficiency, keratinization,
symblepharon, eyelid abnormalities that would preclude stable tear film but cannot be corrected with
surgery, and/or severe limbal stem cell deficiency
and prone to spontaneous corneal necrosis (melt)
should be considered for a Boston Keratoprosthesis
Type II.
B. Decision making: Boston Keratoprosthesis Type I or
II. Examples to be presented.
V. General Complications of the Boston Keratoprosthesis
A. Stromal necrosis and extrusion
B. Infectious keratitis
C. Infectious endophthalmitis
D. Sterile vitritis
E. Retroprosthetic membrane
F. Retinal detachment
G. Glaucoma

VI. Complications of the Boston Keratoprosthesis Specific
to Limbal Stem Cell Failure
A. Limbal stem cell failure is in no way a contraindication to implantation of the Boston Keratoprosthesis
and may be an indication for keratoprosthesis when
corneal clarity is compromised and the likelihood of
successful corneal allograft is low.
B. After Boston Keratoprosthesis Type I, when tear
film is of poor quality and/or quantity, contact lens
may develop deposits that interfere with vision.
Consider hybrid lens alternatives.
C. Difficulty with contact lens retention after Boston
Keratoprosthesis Type I due to existent or progressive foreshortening of fornices and symblepharon
D. Severe trichiasis
E. Stromal necrosis can occur even in patients with
Boston Keratoprosthesis Type II despite complete
eyelid coverage, particularly around keratoprosthesis stem.
| Cornea
F. Glaucoma, particularly in alkali burns, is the greatest obstacle to long-term success in keratoprosthesis
patients.
1. Glaucoma is particularly difficult to treat in
patients with Boston Keratoprosthesis Type II.
a. Topical medications do not penetrate closed
lids, even around keratoprosthesis stem.
b. Oral agents may be contraindicated or not
sufficiently effective.
c. Glaucoma drainage valves have high failure
rate without conjunctival mucosa as covering.
2. Any IOP elevation should be treated aggressively
in any patient with a Boston Keratoprosthesis,
even before any evidence of optic neuropathy
develops.
3. IOP should be targeted lower in patients after
alkali burn than in other patient groups.
Cornea
The Osteo-Odonto-Keratoprosthesis for Management

of Severe Ocular Surface Disease
Osteo-odonto-keratoprosthesis (OOKP) surgery is a technique
used to replace damaged cornea in blind patients for whom
cadaveric corneal transplantation is doomed to failure. Developed some 40 years ago by Strampelli, it uses the patients own
tooth root and alveolar bone to support an optical cylinder.
After a long interval, the technique is finally gaining widespread
recognition by corneal surgeons worldwide as the treatment of
choice for patients with end-stage corneal disease. In the case of a
dry eye, no other device will work nearly as well.
Referral Guidelines for OOKP Surgery

Indications
Patients with bilateral corneal blindness resulting from severe
Stevens-Johnson syndrome, ocular cicatricial pemphigoid, chemical burns, trachoma, dry eyes, or multiple corneal graft failure
may be considered for OOKP surgery. The better, or only, eye
should have poor vision such as PL, HM, or at best CF. One eye
only will be rehabilitated. In suitable cases, there would be no
need to go through unsuccessful penetrating keratoplasty with or
without limbal stem cell transplantation and amniotic membrane
grafting beforehand.
Contraindications
Patients who are happy and managing with their level of vision,
children under the age of 17, eyes that have no perception of
light or that have evidence of phthisis, advanced glaucoma, or
irreparable retinal detachment should be excluded. Suitable candidates have to understand that the surgery can be prolonged
they may require multiple proceduresand that there is a significant risk of serious complications, including loss of the eye.
The patient must be able to commit to lifelong follow-up and not
have unreasonable expectations of outcome and cosmesis.
Patient Assessment
Ophthalmic assessment
In Brighton, patients referred for possible OOKP surgery attend
a joint clinic headed by an ophthalmologist and a maxillofacial
surgeon. In the preoperative assessment we take a detailed history and determine the primary diagnosis and previous surgical
interventions, especially regarding ocular perforation, glaucoma,
or a history of amblyopia. Preoperative examination involves
determining an intact and functioning retina and optic nerve.
This can be by relatively accurate light projection in all quadrants and a normal B-scan. In some cases a flash electroretinogram and visual evoked potential (VEP) can be useful.
The lids and fornices are examined, and the degree of dry eye
is noted, although a severe dry eye is not a contraindicated (as it
is with other forms of KPros). The conjunctiva and cornea are
examined, and evidence of stem cell failure, metaplasia, or dysplasia is noted. Thinning of the cornea and evidence of previous
corneal perforation, iris adhesion, and degree of vascularization
are also noted. The depth of the anterior chamber, if visible, is
noted. The IOP is determined digitally and a record is made as
to whether the eye is phakic, pseudophakic, or aphakic. A- and

B-scans are used for biometry to determine the axial length,
exclude prephthisis, confirm the lens status and exclude retinal
detachment, and detect gross glaucomatous cupping.
Assessment of a patient for OOKP also involves an assessment of the general medical and psychological status of the
patient. The patient must be fully informed of the procedures
and risks. The side effects and possible complications are
described below.
Oral assessment
The oral assessment must take into account both the buccal
mucosal graft donor site and a selection of an appropriate tooth
to form a dentine/bone lamina.
Buccal mucosal assessment
Since a number of patients will need an OOKP due to mucocutaneous diseases, the oral mucosa may be damaged. The extent of
damage has never, in our experience, affected the harvesting of a
graft, but this must still be borne in mind; severe scarring of the
oral mucosa may compromise the successful harvest. Those who
smoke should be advised to stop smoking to improve the chance
of graft revascularization. Betel nut chewing will compromise tissue quality.
Dental assessment
The procedure involves harvesting a tooth and its associated
alveolar bone for fashioning a lamina. The assessment aims
to select a healthy tooth (root) with the best shape and size and
good covering of alveolar bone. The surrounding anatomy is
assessed to avoid possible complications and to reduce the cosmetic defect to a minimum. There also needs to be adequate
space between the teeth to harvest the tooth without damage to
its neighbor. There is sometimes a compromise.
The assessment therefore involves methods of assessing these
factors. The overall oral health, with particular reference to oral
hygiene and periodontal bone loss, must be assessed. Gingival
disease with no bone loss can be easily reversed. Clinical assessment of bone loss can be useful, but radiographs are essential.
The ideal tooth in size and shape with the best surrounding
bone is usually the canine tooth. There is usually little to choose
in these parameters between the upper or lower canine. Other
single-rooted teeth can be used in the absence of a canine.
The assessment of suitability of the tooth depends on clinical
examination but mainly on radiological assessment. The mainstay views are orthopantomograms (OPT) and intraoral periapical radiographs (IOPAs). These views are essential. They give
enough information in the majority of cases. CT scans can be
useful to get more detail and are advocated by some operators.
All other things being equal, the choice of upper or lower
canine depends on the proximity of the maxillary sinus in the
upper and, although this is rarely a problem, the proximity of
the mental foramen in the lower. The lower canine harvesting is
straightforward, but the buccal plate is occasionally a little thin
and the lingual mucoperiosteum is more difficult to preserve.
The upper canine occasionally gives too much bone palatally and
there is the risk of violation of the antrum; however, technically,

the harvesting is easier.
The patient must be given full information at this stage to
give adequate consent. Complications will be dealt with later,
but side effects of the dental part of the procedure, such as the
inevitable gap left in the dentition and the possible methods of
management, should be mentioned at this stage. The patients
regular dental practitioner should be informed at this stage so
that preparation to replace the missing tooth may be made and
so the oral hygiene and periodontal condition can be optimized
preoperatively.
Occasionally, there is no tooth suitable because of deficient
surrounding tissues, and in this circumstance an allograft may be
considered.
Surgical Technique
Stage I
OOKP surgery is usually carried out in two stages. In the
first stage a monoradicular tooth is harvested to prepare an
osteoodonto-lamina. The root and surrounding jaw bone is
sliced sagittally, while the crown is grasped with extraction forceps to expose pulp, which is removed. A hole is drilled through
dentine, through which the anterior part of a PMMA optical cylinder is cemented in place. The crown is removed prior to drying
with filtered oxygen and cementing of the optical cylinder. The
saw, flywheel and drill, and bur tips are constantly irrigated with
balanced salt solution to provide cooling. Where periosteum has
been detached, it is glued back with fibrin glue. The KPro is then
implanted into a submuscular pouch (often the lower eyelid of
the fellow eye) for a period of 2 to 4 months.
A buccal mucous membrane graft is used to cover the OOKP
lamina: it is more physiological than other coverings (ie, fascia
lata, donor sclera, etc.), there are stem cells present, it has proliferating capability, and it is adapted to high bacterial load. It will
be vascularized by the time of Stage 2 surgery and will provide
the blood supply to the bone part of the OOKP lamina. Once
harvested, the fat from the buccal mucous membrane graft is
removed with curved scissors and the graft soaked in an antibiotic solution until required. The eye is prepared by isolating
the recti with stay sutures, a 360-degree peritomy is performed,
and the conjunctiva and tenons are separated from underlying
sclera. Corneal epithelium and Bowman membrane are removed.
The buccal mucosa is then trimmed to obtain an oval piece of
adequate size to fit snugly on the front of the eye. The mucous
membrane graft is sutured onto the side of the insertion of the
4 recti muscles and to the sclera with interrupted 6-0 vicryl. If
possible, the cut edge of the graft should also be sutured to the
conjunctiva.
Fine details of harvesting buccal mucous membrane graft
The buccal graft must be full-thickness mucosa and of an area
large enough to extend from medial to lateral canthi and from
upper to lower lid fornices. This usually means harvesting a graft
of 3 cm in diameter. The mouth is opened with a speculum, the
parotid duct is identified, and local anesthetic with adrenaline is
injected.
A compression type retractor with the inner holder having a
minimum internal diameter of 3 cm can be used. The outline of
the graft is marked, taking into account the parotid duct; this can
usually be accommodated by going below the duct opening. The
mucosa is incised along its circumference, and scissors are intro-
| Cornea
duced under the mucosa to free the graft from the underlying tissue. The graft can then be delivered.
Hemostasis is achieved. There is usually no need for any
sutures, although in Japan, surgeons have been using artificial
mucous membrane to cover the harvest site.
Fine details of harvesting tooth, root, and surrounding
jaw bone
The harvest of the alveolar/dental complex involves the sectioning of bone on either sides and apical to the chosen tooth and
removing the tooth and its surrounding alveolar bone, together
with the associated mucoperiosteum. An incision is made to the
bone and mucoperiosteum elevated from adjacent teeth. The
bone cuts are made between the teeth and below the chosen
tooth with a fine saw, under constant irrigation to minimize any
thermal injury to the lamina. The complex is then removed from
the mouth in readiness to prepare the lamina.
The resulting alveolar defect is covered as best as possible
with adjacent mucosa, but the exposed bone epithelializes very
rapidly. In Japan, surgeons have been covering the defect with
artificial mucous membrane grafting to accelerate wound healing. The patient is advised regarding oral hygiene and diet; hard
food should be avoided for some time. Antibiotics and analgesics
are prescribed.
When not to do ocular surface reconstruction and tooth
harvesting together
If the eye is very dry or there is a risk of the mucous membrane
graft not taking, it may be better to perform Stage I surgery in 2
steps. The mucous membrane graft to the eye is done first, and
it is only when the graft has been shown to be well established
that the patient is readmitted for tooth harvesting and preparing an OOKP lamina. Otherwise, if there is a significant delay
in mucous membrane healing or if further partial or full repeat
mucosal grafting proves necessary, the lamina may be resorbed
while buried in the lid for an excessively long time.
Stage II
Stage II surgery is carried out 2 to 4 months after Stage I in order
for soft tissue to invest into the bone pores of the lamina. The
interval also allows the lamina to recover from thermal damage,
and any infection introduced from the oral cavity can be treated
while the lamina is submuscular rather than on the eye. If the
lamina is implanted submuscularly for a longer period of time,
there may be significant resorption of the lamina. The first step
in Stage II surgery is to retrieve the buried lamina for inspection.
Only if this is of adequate size does the surgeon proceed to preparing the eye for receiving the device. After the OOKP lamina is
retrieved from its submuscular pocket, soft tissue is excised from
the posterior surface and trimmed from the anterior. A template
is made of the lamina in order to plan placement of a Flieringa
ring, and sutures are preplaced for securing the lamina. The
lamina is temporarily returned to its submuscular pocket until
the cornea is about to be trephined.
Traction sutures are applied to the lids for access to the eye.
A superior rectus stay suture is placed and a buccal graft flap
is fashioned by making an arcuate incision from 3 oclock to 9
oclock under constant irrigation with BSS and adrenaline. The
flap is reflected and the cornea exposed. The buccal mucous
flap is then reflected and a Flieringa ring sutured in place, with
sutures left long at 3 and 9 oclock for traction. The center of
the cornea is marked and the template placed on the cornea, and
cardinal sutures are preplaced. Intravenous mannitol has by then
Cornea
been administered to reduce the IOP before trephination. The

cornea is partially trephined, the size depending on the diameter
of the posterior part of the optical cylinder. This is completed
with scissors or a blade. The iris is then completely removed
using forceps. If the patient is phakic, the lens is removed by
extracapsular cataract extraction (ECCE) (Falcinelli advocates
an ICCE). A posterior capsulotomy is made and an anterior
vitrectomy is performed, with adequate traction provided by the
surgical assistant on the two Flieringa ring sutures. The lamina is
then sutured to the cornea with the posterior part of the optical
cylinder traversing the corneal opening. Sterile air is then injected
to reinflate the eye, and indirect funduscopy is performed to
ascertain adequate centration and to take note of the appearance of the posterior pole of the eye and any presence of blood
in the vitreous. Further interrupted sutures are applied to secure
the lamina onto the sclera. The Flieringa ring is then removed
and the buccal mucous membrane is repositioned and sutured in
place, with a hole cut through the membrane to allow the anterior part of the optical cylinder to protrude (see Figures 1 and 2).
Figure 1. Slitlamp photograph of an OOKP eye.
Postoperative Care
The immediate postoperative period requires pain relief, prednisolone 20 mg and lansoprazole 30 mg for 5 days, and oral
antibiotics. After Stage I, a conformer is often in place over the
buccal mucous membrane and daily glass rodding is carried out
to the fornices to keep them open. The patient uses chlorhexidine
and nystatin mouth washes. Post Stage II, Diamox, steroids, and
antibiotics are continued. The optic is cleaned and the health of
the buccal mucous membrane monitored. The skin sutures are
removed after 5 days, and the patient is admitted for 1 week for
each stage.
Follow-up visits
The follow-up is lifelong: at weekly intervals for 1 month, then
monthly for 3 months, then every 2 months for 6 months, then
every 4 months. If stable, then follow-up can be at longer intervals, possibly shared with the referring ophthalmologist. At the
follow-up visits, the vision is checked, unaided and with correction and pinhole, and a refraction performed. The IOP is checked
digitally, the lids are examined, and the buccal mucous membrane is assessed, including color, dryness, and the presence of
any areas of thinning or ulceration. The optical cylinder is examined, specifically looking at the cement to see if there is tilting or
lengthening and to check for the presence of a retroprosthetic
membrane. The stability of the optical cylinder is also tested by
prodding with a cotton-tipped stick. Funduscopy is carried out to
check the optic disk and macula; B-scans are done to detect early
peripheral detachments; and visual field assessments are made
every 6 months for diagnosis and to monitor glaucoma. Resorption of the bone may be assessed clinically by palpating the mass
and dimensions of the lamina and radiologically using spiral CT,
MRI, or electron beam tomography.
If the patient has had an allograft, cyclosporin will be in use.
An empirical serum level of between 100 and 200 ng/ml is aimed
for, and after baseline investigations the urea and electrolytes,
creatinine, and cyclosporin levels are monitored at 3 days, 7
days, fortnightly for 2 months, every month for 4 months, then
every 2 months if stable.
Selected Reading
1. Liu C, Paul B, Tandon R, et al. The osteo-odonto-keratoprosthesis
(OOKP). Semin Ophthalmol. 2005; 20:113-128.
Figure 2. Schematic diagram of cross-section anatomy of an OOKP eye.
Appendix
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17
18
| Cornea
A Biosynthetic Alternative to Human Donor Tissue

Per Fagerholm MD, May Griffith PhD, Neil Lagali PhD
Introduction
Biosynthetic corneal replacements can potentially address two
main problems: (1) the short supply of high-quality transplant
tissue to meet the need, where 10 million people are estimated
to require transplantation and (2) the use of acellular implants
reduced inflammation, and biosynthetics may minimize/eliminate
the risk of rejection, which for PK is 10% within 2 years. The use
of recombinant collagen also eliminates transmission of diseases
such as those caused by viruses and prions.
The biosynthetic implants mimic the extracellular matrix of
the corneal stroma and guide the recipient cells in a healing process that leaves the cornea transparent, with appropriate refractive properties after the healing process.
Background Observations
Implants were made from human recombinant collagen type III
(RHCIII), crosslinked using water soluble carbodiimide (WSC).
After extensive animal workup in several species, we conducted
a human Phase 1 study where the material was implanted into
10 eyes following approvals from the Swedish Medical Products
Agency and the Regional Ethical Review Board in Linkping.
The patients 2-year data have been published,6 and the 3-year
follow-up is presented here.
Materials and Methods

Details of materials and methods were previously reported.6
Briefly, 10 consecutive patients, aged 18-75 years (8 male,
2 female) from a waiting list for a first corneal transplantation
were enrolled. Inclusion criteria included a clear posterior stroma
and normal endothelium. Nine of 10 eyes had a diagnosis of
advanced keratoconus. The tenth eye had a permanent midstromal scar in the visual axis secondary to bacterial keratitis. Ten
longitudinally followed PKP patients served as controls.
Anterior lamellar keratoplasty (ALK) was performed under
either local or general anesthesia. The cornea was trephined to
6.0- to 6.5-mm diameter to a depth of 200 m, and deepened
manually with a diamond knife to 370-400m. Manual lamellar
dissection was then used to remove the corneal tissue. A punch
trephine (Baron, Katena, New Jersey, USA) cut the biosynthetic
implant 500m thick, 0.25mm larger in diameter than the
recipient bed. The implant was anchored with overlying 10-0
nylon mattress sutures. A bandage contact lens was placed. Postoperatively, patients received 1 drop each of chloramphenicol
and Opnol topical steroid drops (0.1% dexamethasone, Clean
Chemical Sweden, Borlnge, Sweden) 3 times daily for a mean
of 6.5 3 weeks, at which time the contact lens and sutures were
removed. One patient underwent successful cataract surgery at
10 months. No episodes of rejection were observed.
All control patients underwent PKP with human donor corneas from Swedish cornea banks. PKP was performed under general or local anesthesia. The 3-year follow-up was completed for
9 out of 10 patients in the human tissue group (6 male, 3 female,

age 56 17 years at surgery). Indication for transplantation in
the human tissue group was keratoconus (5 cases), endothelial
decompensation (2 cases), a deep, central scar (1 case), and pseudophakic bullous keratopathy (1 case). One patient underwent
successful cataract surgery at 12 months, while another exhibited
rejection at 12 months, which resolved after topical dexamethasone treatment. A tenth patient from the human tissue group was
removed from the study after a retinal detachment occurred a
few months postoperatively.
Additionally, a group of 20 healthy volunteers was examined
to establish a reference for normal corneal morphology (healthy
group).
Results
Three years after surgery, the gross appearance of human donor
and biosynthetic tissue was similar (see Figure 1). In all patients,
areas of reduced transparency were observed. In the human
donor group, prominent haze was observed at the peripheral
host-graft interface, while all central corneas were transparent. In
the biosynthetic group, all corneas had peripheral host-implant
interface haze, but with a less discernible implant-host border.
An additional posterior lamellar interface haze was also present,
and 8 out of 10 biosynthetic implants also had focal areas of
haze in the midperipheral to central cornea.
We believe the haze within the central cornea was due to the
disruption of re-epithelialization by the tight overlying sutures, as
the pattern of haze corresponded to the position of earlier overlying sutures. These areas were first noted at the time of suture
removal and persisted to 36 months. The corneal thickness is
indicated in Figure 2.
The BCVA was not impressive, but the patients improved
considerably when fitted with contact lenses (see Figure 3).
Figure 1. Corneal appearance by slitlamp biomicroscopy 36 months

after surgery. Top row: human donor corneas; bottom row: biosynthetic
corneas. Peripheral to midperipheral haze is evident at the graft border in
human tissue (A-C, arrows), with some grafts exhibiting good transparency throughout (D). In biosynthetic tissue, posterior lamellar interface
haze (E, arrowhead) and central foci of haze (E-G, arrows) were evident,
while some implants remained substantially transparent (H).
Cornea
19
Conclusions
The results from the Phase 1 study was reasonably successful. We also have identified problems that will be addressed
in a Phase 2 study. We have increased the collagen content of
the construct in order to make the material mechanically more
robust, allowing for use of peripheral interrupted sutures that
will leave the central cornea undisturbed. We also aim to evaluate the anti-inflammatory effect of using an amniotic membrane.
Likewise, a keratoconus group will be compared to a nonkeratoconus group (dystrophies, scars, etc). Part of this concept has
been successfully tested in minipigs.
References
Figure 2. Corneal thickness in the central 2mm of cornea in operated

groups and in a healthy group of volunteers, measured by anterior segment OCT (AS-OCT). Markers indicate mean thickness values in the
group, while error bars represent 1 standard deviation. Mean corneal
thickness was assessed by AS-OCT. In the human donor group, a significant thickness increase occurred from 12 to 24 months (Wilcoxon signed
rank test, P = .008) but stabilized thereafter. At 36 months, they were
significantly thicker than healthy corneas (t test, P = .021). No change
in central thickness could be detected in the biosynthetic group (1-way
ANOVA, P = .98). They were significantly thinner than human donor
corneas and healthy groups (Mann-Whitney, P < .001).
1. Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a

global perspective. Bull World Health Organ. 2001; 79:214-221.
2. Claesson M, Armitage WJ, Fagerholm P, Stenevi U. Visual outcome
in corneal grafts: a preliminary analysis of the Swedish Corneal
Transplant Register. Br J Ophthalmol. 2002; 86:174-180.
3. Merrett K, Fagerholm P, McLaughlin CR, et al. Tissue engineered
recombinant human collagen-based corneal substitutes for implantation: performance of type I versus type III collagen. Invest Ophthalmol Vis Sci. 2008; 49:3887-3894.
4. Lagali N, Griffith M, Fagerholm P, Merrett K, Huynh M, Munger
R. Innervation of tissue-engineered recombinant human collagenbased corneal substitutes: a comparative in-vivo confocal microscopy study. Invest Ophthalmol Vis Sci. 2008; 49:3895-3902.
5. Liu W, Merrett K, Griffith M, et al. Recombinant human collagen for tissue engineered corneal substitutes. Biomaterials 2008;
29(9):1147-1158.
6. Fagerholm P, Lagali NS, Merrett K, et al. A biosynthetic alternative
to human donor tissue for inducing corneal regeneration: 24-month
follow-up of a phase 1 clinical study. Sci Transl Med. 2010;
2(46):46ra61.
Figure 3. The mean BSCVA in logMAR units over time. There is some
improvement over the first 18 months. The BCLVA, however, is considerably better, as depicted after 24 months.
20
| Cornea
Oral Mucosal Epithelial Transplantation for the

Management of Ocular Surface Disease
Corneal Reconstruction With Autologous Oral Mucosal Epithelial Cell Sheets

Kohji Nishida MD
Drastic progress of the understanding of stem cell biology
occurred in the 1990s, and the clinical usage of stem cells seems
to be promising. Recently, a novel therapeutics utilizing tissue
engineering and stem cell technology, called regenerative medicine, has been emphasized. As regenerative medicine for corneal
epithelial diseases, transplantation of cultivated corneal epithelial
cell sheets fabricated from corneal epithelial stem cells expanded
ex vivo has been developed and has already entered the clinical
realm.
In this presentation, I will talk on corneal reconstruction
with autologous oral mucosal epithelial cell sheets. We have
developed this technique and performed a clinical application
for patients who suffered from severe limbal stem cell deficiency.
The outline of my talk is described below.
I. Corneal Stem Cells and Diseases With Stem Cell
Deficiency
A. Concept of corneal epithelial stem cell
II. Introduction of Cultivated Corneal Epithelial Cell

Transplantation
A. Several approaches for cultivated corneal epithelial
cell transplantation
B. Disadvantage of cultivated corneal epithelial cell
transplantation
III. A Novel Tissue Engineering Approach: Cell Sheet
Engineering
A. What is cell sheet engineering?
B. How to manipulate epithelial stem cells in vitro
C. Advantage of cell sheet engineering
IV. Corneal Epithelial Reconstruction With Cell Sheets
A. Cell source and basic data
B. Limbal stem cell deficiency
B. Advantage of cell sheet engineering for corneal epithelial reconstruction
C. Corneal epithelial stem cell transplantation
C. Surgical procedure
D. Indication and clinical data
Cornea
21
Cultivated Limbal Epithelial Transplantation for the

Management of Ocular Surface Disease
Background
The corneal surface is maintained by a steady supply of epithelial
cells from the limbus that surrounds it.1 There is now enough
clinical and scientific evidence to suggest that adult corneal epithelial stem cells reside at that location.2,3 Ocular trauma or surface disease can damage the limbus, leading to a functional loss
of these stem cells and consequently inducing corneal epithelial
instability.4,5 This condition, termed limbal stem cell deficiency
(LSCD), is clinically characterized by the loss of corneal epithelial clarity, loss of vision, and recurrent or persistent epithelial
defects.4,5 Conventional corneal transplantation is not successful
in such eyes as there is insufficient supply of endogenous recipient limbus-derived epithelium to maintain the graft.6,7
Origin of Stem CellBased Therapy for LSCD

Kenyon and Tseng provided proof-of-principle that transplantation of stem cellbearing limbal tissue could cure LSCD.8 Since
then, direct limbal transplantation from the unaffected fellow eye
(autologous) or from donors (allogenic) has become standard of
care for LSCD.8-16 However, direct transplantation requires at
least 4 clock hours (3x10 mm) of donor limbal tissue,8-16 which
can lead to donor site iatrogenic LSCD.9,15,16
Current Status of Stem CellBased Therapy for

LSCD
Ex vivo expansion of the limbal epithelium is a novel therapeutic
approach to treat LSCD. This requires relatively smaller (2x1
mm) donor tissue, thus eliminating the risk of inducing iatrogenic LSCD in the donor eye. The first report of the culture of
corneal epithelial cells with murine feeder cells came from Pel-
legrini et al in 1997.17 Since then, many modifications of this

original technique using different culture systems and carriers
have been reported in the literature.18,19
LVP Technique and Outcomes

We have developed novel and successful modifications in the
procedure, namely, a feeder-free explant culture system, use of
human autologous (rather than animal based) serum, and human
recombinant growth factors (see Figure 1). Over the course of
the last decade we have characterized the cultured cells,20 standardized our cultivation technique,21 and reported encouraging
early results of clinical transplantation.22,23 Earlier we reported
our short-term results in 88 eyes with a success rate of 73%,23
which is comparable to other large studies by Rama et al (107
eyes, 68%)24 and Di Ioro et al (166 eyes, 80%).25 Successful
outcome was noted in 279 of 444 eyes (62.8%), and probability
of survival for autologous cultivated limbal epithelium transplantation (CLET) was 65% at 1 year, with median survival of 4.3
years (our unpublished data).
Outcomes of Autologous Cultivated Limbal

Epithelial Transplantation
This study included 444 eyes of 435 patients who underwent
autologous CLET for clinically diagnosed LSCD due to ocular
burns between April 2001 and November 2010. The primary
outcome measure was clinical success of the transplantation,
defined as the achievement of a stable corneal surface. Failure
was defined as superficial corneal vascularization, conjunctivalization, and/or recurrent epithelial breakdown. Results were
analyzed using Kaplan Meier survival analysis. The secondary
Figure 1.
22
outcome measure was improvement in best spectacle corrected

visual acuity (BSCVA). Most patients were young (median age:
20 years) males (75.6%) with ocular chemical burns (88.5%),
unilateral LSCD (92.2%), and severe visual loss (76.6%). The
median postsurgical follow-up was 1.2 years, with a maximum
follow-up of 7.2 years.
CLET was successful in 279 of 444 eyes (62.8%; median
survival of 4.3 years). Most (76.9%) failures occurred within the
first 8 months. Subgroup analysis showed that success of CLET
was significantly better (81.5%, P = .012) in eyes without previous corneal surgeries, poor preoperative BSCVA (<20/200),
and simultaneous keratoplasty. Among 279 successful cases, a
2-line improvement of BSCVA was seen in 183 eyes (65.6%; P <
.0001) and 124 eyes (44.4%) achieved BSCVA of 20/60 or better. No serious ocular complications were noted in transplanted
or donor eyes. In this large series, autologous CLET was effective
in restoring ocular surface stability and improving vision in eyes
with LSCD caused by ocular surface burns (see Figure 2).
Figure 2. Survival curve for outcome of CLET.
was 76.9% 11.7% at 12 months, with median survival of 40

months. No donor or recipient eyes developed serious ocular
complications. Visual acuity improved to 20/60 or better in 7
eyes after allo-CLET alone, and in 11 other eyes following PK.
Ocular surface stability and visual restoration can be successfully achieved in eyes of patients with bilateral total LSCD by
performing allo-CLET followed by PK.
Outcomes of Penetrating Keratoplasty After

Autologous Cultivated Limbal Epithelial
Transplantation
This study included 47 patients with unilateral limbal stem cell
deficiency (LSCD) due to ocular surface burns, treated by autologous cultivated limbal epithelial transplantation and PK between
2001 and 2010. PK was performed either along with (singlestage, n = 12) or at least 6 weeks after (2-stage, n = 35) limbal
transplantation. Primary outcome measure was corneal allograft
survival, and failure was clinically defined as loss of central graft
clarity. Secondary outcomes were postoperative Snellen visual
acuity and complications. Most patients were young (mean age:
18 11.4 years) males (76.6%) with LSCD due to alkali burns
(78.7%) and vision less than 20/200 (91.5%). The mean followup was 4.2 1.9 years.
Kaplan-Meier corneal allograft survival rate at 1 year was significantly greater in eyes undergoing 2-stage (80% 6%, median
survival: 4 years) as compared to single-stage (25% 13%,
median survival: 6 months) limbal and corneal transplantation (P
= .0003). Visual acuity of 20/40 or better was attained by 71.4%
of eyes with clear corneal grafts. Allograft failure occurred in
26 eyes (60.5%) due to graft rejection (57.7%), graft infiltrate
(26.9%), or persistent epithelial defects (15.4%). Recurrence of
LSCD was more common after single-stage (58.3%) than 2-stage
(14.3%) surgery (P = .008).
Two-stage approach of autologous cultivated limbal epithelial transplantation followed by PK successfully restores ocular
surface stability and vision in eyes with unilateral LSCD due to
ocular burns. Single-stage approach is associated with poorer
clinical outcomes and should be avoided.
Outcomes of Allogenic Cultivated Limbal Epithelial

Transplantation
This study included 28 eyes of 21 patients with bilateral clinically diagnosed total LSCD who were treated between January
1, 2001, and January 1, 2010. All patients developed corneal
blindness after the age of 8 years and had at least 6 weeks of
postsurgical follow-up. The primary outcome was maintenance
of a clinically stable ocular surface, and failure was defined as
the formation of a persistent epithelial defect, diffuse fluorescein
staining, or central corneal neovascularization. Secondary outcomes were visual acuity, complications, and survival of subsequent corneal allografts. The mean age at the time of allo-CLET
was 27.9 14.7 years, with male-to-female ratio of 4.25:1. The
median time between the initial injury and allo-CLET was 38
months (range: 3-432). Most eyes (61%, n = 17) had history of
chemical or thermal injury, and preoperative vision ranged from
20/100 to light perception.
The Kaplan-Meier allo-CLET survival rate at 12 months was
76.4% 8.7%, with mean follow-up of 58 33 months. At
last follow-up, 20 eyes (71.4%) had either maintained a healthy
corneal surface or underwent penetrating keratoplasty (PK).
The corneal allograft survival rate following allo-CLET (n = 13)
| Cornea
Figure 3. Survival curve for PK after CLET.
Cornea
Outcomes of Repeat Autologous Cultivated Limbal

Epithelial Transplantation
To evaluate the outcomes of repeat autologous cultivated limbal
epithelial transplantation (CLET) after failed primary CLET for
limbal stem cell deficiency (LSCD). This study was a retrospective chart review of 68 eyes of 68 patients who underwent repeat
autologous CLET for unilateral LSCD due to ocular surface
burns between 2001 and 2009. A limbal biopsy was obtained
from the healthy contralateral eye. The limbal epithelial cells
were expanded ex vivo on human amniotic membrane using a
xeno-free and feeder-free culture system. The resulting cultured
monolayer sheet was transplanted on the patients affected eye
after surgical preparation. All patients underwent a comprehensive ophthalmic examination of both eyes at every visit. Primary
outcome measure was success of repeat CLET, clinically defined
as stable ocular surface with absence of conjunctivalization or
peripheral corneal neovascularization at 1 year postoperatively.
Most patients were young (mean age: 17.3 12.3 years) males
(72.1%) with history of alkali burns (83.8%) and median follow-up of 19 (range: 12 to 90) months.
Kaplan Meier survival probability of repeat autologous CLET
was 46.3% 0.07% at 1 year (median survival: 10 months).
Subgroup analysis showed that success of CLET was significantly better (80.4%, P = .0004) in eyes without symblepharon
(hazard ratio: 4.6) and simultaneous keratoplasty (hazard ratio:
2.6). In 82% of successful cases vision improved to 20/40 or better postoperatively (P < .0001). All donor eyes had normal ocular surface postoperatively.
Autologous CLET is safely repeatable and is effective in
treating eyes with failed primary CLET and LSCD due to ocular
surface burns.
Conclusions
Cultivated limbal epithelial transplantation (CLET) is safe and
effective procedure for total or partial LSCD. Significant percentages of patients show improved ocular surface and vision on a
long-term basis.
References
1. Shapiro MS, Friend J, Thoft RA. Corneal re-epithelialization from
the conjunctiva. Invest Ophthalmol Vis Sci. 1981; 21:135-142.
2. Schermer A, Galvin S, Sun T-T. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests
limbal location of corneal epithelial stem cells. J Cell Biol. 1986;
103:49-62.
3. Shanmuganathan VA, Foster T, Kulkarni BB, et al. Morphological characteristics of the limbal epithelial crypt. Br J Ophthalmol.
2007; 91:514-519.
4. Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol. 2000; 44:415-425.
5. Tseng SC. Concept and application of limbal stem cells. Eye 1989;
3:141-157.
6. Maguire MG, Stark WJ, Gottsch JD, et al; Collaborative Corneal
Transplantation Studies Research Group. Risk factors for corneal
graft failure and rejection in the collaborative corneal transplantation studies. Ophthalmology 1994; 101(9):1536-1547.
23
7. Brown SI, Bloomfield SE, Pearce DB. Follow-up report on transplantation of the alkali burned cornea. Am J Ophthalmol. 1974;
77:538-542.
8. Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular
surface disorders. Ophthalmology 1989; 96:709-722.
9. Miri A, Said DG, Dua HS. Donor site complications in autolimbal
and living-related allolimbal transplantation. Ophthalmology.
Epub ahead of print 30 Mar 2011.
10. Miri A, Al-Deiri B, Dua HS. Long-term outcomes of autolimbal and
allolimbal transplants. Ophthalmology 2010; 117(6):1207-1213.
11. Santos MS, Gomes JA, Hofling-Lima AL, Rizzo LV, Romano AC,
Belfort R Jr. Survival analysis of conjunctival limbal grafts and
amniotic membrane transplantation in eyes with total limbal stem
cell deficiency. Am J Ophthalmol. 2005; 140(2):223-230.
12. Ozdemir O, Tekeli O, Ornek K, Arslanpene A, Yalindag NF.
Limbal autograft and allograft transplantations in patients with
corneal burns. Eye (Lond). 2004; 18(3):241-248.
13. Dua HS, Azuara-Blanco A. Autologous limbal transplantation in
patients with unilateral corneal stem cell deficiency. Br J Ophthalmol. 2000; 84:273-278.
14. Rao SK, Rajagopal R, Sitalakshmi G, Padmanabhan P. Limbal allografting from related live donors for corneal surface reconstruction.
Ophthalmology 1999; 106:822-828.
15. Basti S, Mathur U. Unusual intermediate-term outcome in three
cases of limbal autograft transplantation. Ophthalmology 1999;
106(5):958-963.
16. Tan DT, Ficker LA, Buckley RJ. Limbal transplantation. Ophthalmology 1996; 103(1):29-36.
17. Pellegrini G, Traverso CE, Franzi AT, Zingirian M, Cancedda R,
De Luca M. Long-term restoration of damaged corneal surfaces
with autologous cultivated corneal epithelium. Lancet 1997;
349:990-993.
18. Shortt AJ, Secker GA, Notara MD, et al. Transplantation of ex
vivo cultured limbal epithelial stem cells: a review of techniques and
clinical results. Surv Ophthalmol. 2007; 52:483-502.
19. Baylis O, Figueiredo F, Henein C, Lako M, Ahmad S. 13 years of
cultured limbal epithelial cell therapy: a review of the outcomes.
JCell Biochem. 2011; 112:993-1002.
20. Polisetti N, Agarwal P, Khan I, et al. Gene expression profiles of
epithelial cells and mesenchymal cells derived from limbal explant
culture. Mol Vis. 2010; 16:1227- 1240.
21. Mariappan I, Maddileti S, Savy S, et al. In vitro culture and expansion of human limbal epithelial cells. Nat Protoc. 2010; 5:14701479.
22. Sangwan VS, Matalia HP, Vemuganti GK, et al. Early results of
penetrating keratoplasty after cultivated limbal epithelium transplantation. Arch Ophthalmol. 2005; 123:334-340.
23. Sangwan VS, Matalia HP, Vemuganti GK, et al. Clinical outcome
of autologous cultivated limbal epithelium transplantation. Indian J
Ophthalmol. 2006; 54:29-34.
24. Rama P, Matuska S, Paganoni G, et al. Limbal stem-cell therapy
and long-term corneal regeneration. N Engl J Med. 2010; 363:147155.
25. Di Iorio E, Ferrari S, Fasolo A, et al. Techniques for culture and
assessment of limbal stem cell grafts. Ocul Surf. 2010; 8:146-153.
24
| Cornea
Ocular Surface Reconstruction With Immature Dental

Pulp Stem Cell Transplantation
Jos AP Gomes MD
Introduction: Challenges in the Treatment of
Bilateral Limbal Stem Cell Deficiency
Limbal epithelial stem cells (LSC), which reside in the transition
area between the cornea and the sclera, are capable of promoting
constant renewal of the corneal epithelium and its regeneration
in case of injury.1-3
A variety of diseases, such as Stevens-Johnson syndrome,
chemical burn, and ocular cicatricial pemphigoid, may cause partial or total limbal stem cell deficiency (TLSCD).1 As a result of
such deficiency, the conjunctival epithelium invades the cornea
in a process known as conjunctivalization, which predisposes to
corneal neovascularization and opacification.2,3 In TLSCD, conjunctivalization usually compromises the visual axis, leading to a
significant loss of visual acuity.2,3
When TLSCD is unilateral, limbal epithelial cell transplantation (CLAU) from the contralateral healthy eye can restore
normal corneal epithelium and decrease neovascularization
and inflammation, leading to improvement of corneal transparency.2-4 This procedure cannot be applied to patients with
bilateral LSCD. In this case, transplant is obtained from a living
related (lr-CLAL) or cadaveric eye (KLAL).5,6 The success of
such grafts is limited by microenvironmental factors as found in
severe dry eyes and by immunologic rejection for the allogeneic
transplanted cells.5,6
Other autologous epithelia such as the conjunctiva have also

been successfully cultivated and transplanted experimentally for
the same purpose.14-16
Searching for another alternative stem cell source that could
be potentially used in corneal reconstruction, we turned our
attention to a population of stem cells isolated by our group
from deciduous teeth, which were named human immature dental pulp stem cells (hIDPSC).
Background Observations: hIDPSC

hIDPSC exhibit all characteristics of multipotent adult stem cells,
expressing mesenchymal stem cell and several human embryonic
stem (ES) cell markers.17-20 Additionally, hIDPSC have a normal
karyotype and show the capacity for multilineage differentiation into neurons, smooth and skeletal muscle, cartilage, bone,
and other cell types in vitro and in vivo.20 We verified LSC gene
expression profile in undifferentiated hIDPSC.21 These undifferentiated cells continuously expressed markers of LSC such as
ABCG2, 1-integrin, vimentin, p63, connexin 43, and keratin
12, but they were negative for the corneal cell marker keratin K3
when cultured in vitro.21
In order to determine the outcome of the use of a tissueengineered cell sheet composed of hIDPSC for ocular surface
reconstruction, we established two different models of TLSCD
induced by chemical injury with 0.5 M NaOH in rabbit eyes.22
After 1 month of injury, a superficial keratectomy was performed to remove the fibrovascular pannus that covered the
animals burned corneas, and a tissue-engineered hIDPSC sheet
was transplanted onto the corneal bed and then covered with
de-epithelialized human amniotic membrane (AM).22 In the
respective control groups, the denuded cornea was covered with
AM only. After 3 months, a detailed analysis of the rabbit eyes
was performed with regard to clinical aspect, histology, electron
microscopy, and immunohistochemistry.22
Figure 1. Survival curve of eyes with TLSCD after conjunctival limbal

graft and amniotic membrane transplantation according to HLA compatibility of the recipient and the donor of the conjunctival/limbal graft.6
Advances in tissue culture and bioengineering have allowed

the ex vivo expansion of limbal epithelial cells using different
scaffolds, including amniotic membrane, fibrin gel, or collagen
contact lenses.7-10 Functional reconstruction of cornea in TLSCD
by limbal epithelial autograft transplantation has been successfully achieved.7-10 Encouraging outcomes with ex vivo allogeneic
LSC transplantation in TLSCD eyes have been reported; however, the problem of graft rejection needs to be overcome.7-10 In
an attempt to avoid rejection, autologous oral mucosal epithelial
cells have been successfully transplanted in LSCD by Nishida et
al using an elegant technique of epithelial cell cultivation on temperature-responsive polymer poly(N-isopropylacrylamide).11-13
Figure 2. Transplantation of tissue-engineered cell sheet made from

undifferentiated hIDPSC. A, Morphology of hIDPSC (phase contrast,
PC). B, Three days after reaching confluence, cells form a cell sheet (PC).
C, The viable cell sheet is harvested by reducing the temperature to 20
degrees C for 30 minutes. D, Sheet of tissue-engineered hIDPSC (arrow)
is harvested with the use of a doughnut-shaped supporter (white). E,
Conjunctival tissue over the cornea is surgically removed to expose transparent corneal stroma. F, Sheet of tissue-engineered hIDPSC is placed on
the stromal bed. G, The sheet adheres to the corneal stroma and the supporter is removed. H, Amniotic membrane is placed over cell sheet and
sutured.22 Scale bar (A-B) = 5 m.
Cornea
Corneal transparency of the rabbit eyes that underwent

hIDPSC transplantation was improved throughout the followup, while the control corneas developed total conjunctivalization and opacification.22 The clinical data were confirmed by
histologic analysis that showed healthy uniform corneal epithelia, especially in the mild chemical burn group.22 The presence
of hIDPSC was detected using an anti-hIDPSC antibody. The
corneal tissue also showed positive immunostaining with antihuman antibodies. In the control corneas, none of these antigens
were detected.22
25
in eyes with total limbal stem cell deficiency. Am J Ophthalmol.

2005; 140:223-230.
7. Pellegrini G, Traverso CE, Franzi AT, et al. Long term restoration
of damaged corneal surface with autologous cultivated corneal epithelium. Lancet 1997; 349:990-993; comment: 1556.
8. Tsai RJ-F, Li LM, Chen J-K. Reconstruction of damaged corneas by
transplantation of autologous limbal epithelial cells. N Engl J Med.
2000; 343(2):86-93.
9. Koizumi N, Inatomi T, Suzuki T, et al. Cultivated corneal epithelial
stem cell transplantation in ocular surface disorders. Ophthalmology 2001; 108:1569-1574.
10. Du Y, Chen J, Funderburgh JL, et al. Functional reconstruction of
rabbit corneal epithelium by human limbal cells cultured on amniotic membrane. Mol Vis. 2003; 9:635-643.
11. Nishida K, Yamato M, Hayashida Y, et al. Functional bioengineered corneal epithelial sheet grafts from corneal stem cells
expanded ex vivo on a temperature-responsive cell culture surface.
Transplantation 2004; 77:379-385.
12. Nishida K, Yamato M, Hayashida Y, et al. Corneal reconstruction
with tissue-engineered cell sheets composed of autologous oral
mucosal epithelium. N Engl J Med. 2004; 351(12):1187-1196.
Figure 3. Representative figures of rabbit eyes 1 month after ocular surface damage and 3 months after transplantation of a tissue-engineered
hIDPSC sheet.22
Preliminary Results: Clinical Experience With

hIDPSC Transplantation for Total Stem Cell
Deficiency
In 2010, we obtained the approval of the Institutional Review
Board and the Brazilian Committee for Ethics in Research to
start the first cases of hIDPSC transplantation for ocular surface
reconstruction in TLSCD. The preliminary results will be presented in this session.
Conclusion
Overall, these data suggest that transplantation of a tissueengineered hIDPSC sheet may represent a potential option for
reconstruction of the corneal epithelium in TLSCD.
References
1. Kruse FE. Classification of ocular surface disease. In: Holland EJ,
Mannis MJ, eds., Ocular Surface Disease: Medical and Surgical
Management. New York: Springer-Verlag; 2001:16-36.
2. Tsubota K. Ocular surface management in corneal transplantation,
a review. Jpn J Ophthalmol. 1999; 43(6):502-508.
3. Dua HS, Azuara-Blanco A. Autologous limbal transplantation in
patients with unilateral corneal stem cells deficiency. Br J Ophthalmol. 2000; 84:273-278.
4. Kenyon KR, Tseng SCG. Limbal autograft transplantation for ocular surface disorder. Ophthalmology 1989; 96:709-722; discussion:
722-723.
5. Tseng SC, Prabhasawat P, Barton K. Amniotic membrane transplantation with or without limbal allografts for corneal surface
reconstruction in patients with LSCs cell deficiency. Arch Ophthalmol. 1998; 116:431-441.
6. Santos MS, Gomes JAP, Hfling-Lima AL, et al. Survival analysis of
conjunctival limbal grafts and amniotic membrane transplantation
13. Kinoshita S, Koizumi N, Nakamura T. Transplantable cultivated

mucosal epithelial sheet for ocular surface reconstruction. Exp Eye
Res. 2004; 78(3):483-491.
14. Tan D, Ang L, Beuerman R. Reconstruction of the ocular surface
by transplantation of a serum-free derived cultivated conjunctival
equivalent. Transplantation 2004; 77(11):1729-1734.
15. Kinoshita S, Tanioka H, Kawasaki S, et al. Establishment of cultivated human conjunctival epithelium as an alternative tissue source
for autologous corneal epithelial transplantation. Invest Ophthalmol Vis Sci. 2006; 47(9):3820-3827.
16. Ang LP, Tanioka H, Kawasaki S, et al. Cultivated human conjunctival epithelial transplantation for total limbal stem cell deficiency.
Invest Ophthalmol Vis Sci. 2010; 51(2):758-764.
17. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem
cells suppress lymphocyte proliferation in vitro and prolong skin
graft survival in vivo. Exp Hematol. 2002; 30:42-48.
18. Rasmusson I, Ringdn O, Sundberg B, Le Blanc K. Mesenchymal
stem cells inhibit the formation of cytotoxic T lymphocytes, but not
activated cytotoxic T lymphocytes or natural killer cells. Transplantation 2003; 76:1208-1213.
19. Ma Y, Xu Y, Xiao Z, et al. Reconstruction of chemically burned rat
corneal surface by bone marrow derived human mesenchymal stem
cells. Stem Cells 2006; 24:315-321.
20. Kerkis I, Kerkis A, Dozortsev D, et al. Isolation and characterization of a population of immature dental pulp stem cells expressing
Oct-4 and other embryonic stem cell markers. Cells Tissues Organs.
2006; 184(3-4):105-116.
21. Monteiro BG, Serafim RC, Melo GB, et al. Human immature dental pulp stem cells share key characteristic features with limbal stem
cells. Cell Prolif. 2009; 42(5):587-594.
22. Gomes JA, Geraldes Monteiro B, Melo GB, et al. Corneal reconstruction with tissue-engineered cell sheets composed of human
immature dental pulp stem cells. Invest Ophthalmol Vis Sci. 2010;
51(3):1408-1414.
26
Section II: Infectious Keratitis
| Cornea
Bacterial Keratitis: Susceptibility Testing, Steroids, and

Other Treatment Controversies
Thomas M Lietman MD
The Importance of Bacterial Keratitis
Corneal opacity has been reported as the fourth leading cause of
blindness globally.1 Much of this is due to infectious ulcers. The
annual occurrence of infectious keratitis has been estimated at
1.5-2 million cases globally, and the true incidence may be much
higher.2 Bacteria such as Streptococcus pneumoniae and Pseudomonas aeruginosa are common etiologic agents of infectious
keratitis, responsible for as much as half of the corneal ulceration
in South India, and typically far larger proportions in the United
States and Europe.3-7 Treatment of bacterial keratitis is difficult
and can lead to poor visual outcomes and blindness, and antimicrobial-resistant bacteria are increasingly found.8
Major issues in treatment of bacterial ulcers include the
importance of susceptibility testing and antibiotic choice, and the
use of adjunctive steroid treatment.
Susceptibility Testing
In systemic bacterial infections, in vitro susceptibility is thought
to predict clinical outcomes.9,10 In ocular infections, since a large
concentration of antibiotic is delivered directly to the site of
infection with application of topical antibiotics, it is possible that
in vitro susceptibility does not play as large a role in determining
clinical outcome.11 Recent studies have suggested that in vitro
susceptibility may predict clinical outcome in bacterial keratitis;
however, the role of organism in this relationship is not clear.12-14
As part of the National Eye Institutefunded Steroids for
Corneal Ulcers Trial (SCUT), we collected minimum inhibitory
concentration (MIC) information for all isolates to moxifloxacin,
the antibiotic used per protocol. Specific clinical outcomes, such
as visual acuity or infiltrate/scar size, were measured precisely,
allowing correction for baseline measurements for each clinical
outcome. This allowed assessment of the MICs effect during the
course of treatment, an analysis that can be difficult to perform
in other disease settings. Here, we will present the relationship
between MIC to moxifloxacin and clinical outcomes (acuity,
scar size, and time to re-epithelialization), while controlling for
organism as well as baseline clinical measurements. A higher
MIC was significantly associated with poorer outcomes, including worse acuity (~1 letter per 2-fold dilution in MIC), worse
scar (0.03mm larger in diameter), and longer re-epithelialization
(hazard ratio = 0.92). These results indicate that while in vitro
susceptibility testing correlates with clinical outcome, MIC itself
explains only a small portion of the overall variance in outcome
(estimated with mediation analysis as 13% of total outcome
variance).
Corticosteroid Use in Bacterial Keratitis

The use of topical corticosteroids as adjunctive therapy in the
treatment of bacterial corneal ulcers has been debated extensively
over the past few decades. Corticosteroids are thought to reduce
immune-mediated damage and have been shown to be beneficial
in some systemic bacterial infections.15-17 The American Academy of Ophthalmology suggests that while there may be a role
for corticosteroids in the treatment of bacterial corneal ulcers,

there is insufficient evidence to make an official recommendation.18 To date, the only evidence available to guide decisions are
animal and retrospective studies, and 2 small clinical trials that
were too underpowered to definitively answer the question.19,20
Therapeutic Exploratory Study for SCUT

The primary objective of the Steroids for Corneal Ulcers Trial
(SCUT) is to assess the impact of adjunctive topical corticosteroids on clinical outcomes in patients with bacterial corneal
ulcers. Forty-two patients were enrolled, treated with moxifloxacin, and treated with either 1% prednisolone phosphate or
placebo (in a masked manner). Acuity and scar size were slightly
better in the steroid-treated cases, although not significantly
so. Re-epithelialization was significantly delayed in the steroidtreated cases. There was no increase in adverse outcomes (such
as perforation) in the steroid arm.20
Therapeutic Confirmatory SCUT

In 2006, the Proctor Foundation at the University of California,
San Francisco, Dartmouth Medical School, and the Aravind Eye
Care System started an NEI-sponsored randomized controlled
trial evaluating the effect of prednisolone phosphate on outcome
in bacterial keratitis. As with the therapeutic exploratory trial, all
cases were treated with topical moxifloxacin. Enrollment of 500
cases was completed in February 2010, and 12-month follow-up
was completed in early 2011. Results of this study will be presented as allowed by NEI regulations.
References
1. Resnikoff S, Pascolini D, Etyaale D, et al. Global data on visual
impairment in the year 2002. Bull World Health Organ. 2004;
82(11):844-850.
2. Whitcher J, Srinivasan M, Upadhyay M. Corneal blindness: a
global perspective. Bull World Health Organ. 2001; 79:214-221.
3. Bourcier T, Thomas F, Borderie V, Chaumeil C, Laroche L. Bacterial keratitis: predisposing factors, clinical and microbiological
review of 300 cases. Br J Ophthalmol. 2003; 87:834-838.
4. Srinivasan M, Gonzales C, George C, et al. Epidemiology and aetiological diagnosis of corneal ulceration in Madurai, South India. Br J
Ophthalmol. 1997; 81:965-971.
5. Varaprasathan G, Miller K, Lietman T, et al. Trends in the etiology
of infectious corneal ulcers at the F.I. Proctor Foundation. Cornea
2004; 23:360-364.
6. Bharathi MJ, Ramakrishnan R, Meenakshi R, Padmavathy S,
Shivakumar C, Srinivasan M. Microbial keratitis in South India:
influence of risk factors, climate, and geographical variation. Ophthalmic Epidemiol. 2007; 14(2):61-69.
7. Leck A, Thomas P, Hagan M, et al. Aetiology of suppurative corneal ulcers in Ghana and south India, and epidemiology of fungal
keratitis. Br J Ophthalmol. 2002; 86:1211-1215.
Cornea
8. Alexandrakis G, Alfonso E, Miller D. Shifting trends in bacterial

keratitis in south Florida and emerging resistance to fluoroquinolones. Ophthalmology 2000; 107(8):1497-1502.
9. Rex J, Pfaller M. Has antifungal susceptibility testing come of age?
Clin Infect Dis. 2002; 35:982-989.
10. Weinstein M, Reller L, Murphy J, Lichtenstein K. The clinical significance of positive blood cultures: a comprehensive analysis of
500 episodes of bacteremia and fungemia in adults. I. Laboratory
and epidemiologic observations. Rev Infect Dis. 1983; 5(1):35-53.
27
15. Schoeman J, Van Zyl L, Laubscher J, Donald P. Effect of corticosteroids on intracranial pressure, computed tomographic findings,
and clinical outcome in young children with tuberculous meningitis.
Pediatrics 1997; 99(2):226-231.
16. Girgis N, Farid Z, Mikhail I, Farrag I, Sultan Y, Kilpatrick M.
Dexamethasone treatment for bacterial meningitis in children and
adults. Pediatr Infect Dis J. 1989; 8(12):848-851.
17. Lebel M, Freji B, Syrogiannopoulos G, et al. Dexamethasone therapy for bacterial meningitis. New Engl J Med. 1988; 319:964-971.
11. Baum J, Barza M. The evolution of antibiotic therapy for bacterial

conjunctivitis and keratitis: 1970-2000. Cornea 2000; 19(5):659672.
18. American Academy of Ophthalmology Cornea/External Disease

Panel. Preferred Practice Pattern Guidelines: Bacterial Keratitis. San
Francisco, CA: American Academy of Ophthalmology; 2008.
12. Chen A, Prajna L, Srinivasan M, et al. Does in vitro susceptibility

predict clinical outcome in bacterial keratitis? Am J Ophthalmol.
2008; 145:409-415.
19. Carmichael T, Gelfand Y, Welsh N. Topical steroids in the treatment of central and paracentral corneal ulcers. Br J Ophthalmol.
1990; 74:528-531.
13. Kaye S, Tuft S, Neal T, et al. Bacterial susceptibility to topical antimicrobials and clinical outcome in bacterial keratitis. Invest Ophthalmol Vis Sci. 2010; 51(1):362-368.
20. Srinivasan M, Lalitha P, Mahalakshmi R, et al. Corticosteroids for

bacterial corneal ulcers. Br J Ophthalmol. 2009; 93(2):198-202.
14. Wilhelmus K. Evaluation and prediction of fluoroquinolone pharmacodynamics in bacterial keratitis. J Ocul Pharmacol Ther. 2003;
19:493-439.
28
| Cornea
An Evidence-Based Approach to Managing

Fungal Keratitis
Introduction and Magnitude of Fungal Corneal Ulcers
In some geographic regions, fungus is responsible for as much as
half of all corneal ulcers and the incidence may be increasing.1-4
While the incidence of fungal keratitis historically is lower in
temperate climates,5,6 a recent outbreak of Fusarium keratitis in
the United States and Asia heightened global awareness of fungal
keratitis and underscored the need to find evidence-based treatment practices for these patients.7 Fungal keratitis frequently
leads to poor outcomes, so the need for early, effective treatment
is great. In this presentation, I will discuss the evidence to date
for treating fungal keratitis, and where we are going from here.
Dearth of New Antifungals and Few Randomized,

Controlled Trials
No new antifungals have been approved for ocular fungal infections since the approval of natamycin in the 1960s. Voriconazole, a newer triazole, has been shown to have good in vitro
efficacy against certain filamentous fungi8; however, it remains
unclear whether voriconazole is as good as the commercially
available natamycin in treating fungal corneal ulcers. To date,
there have been only 2 published, randomized, controlled trials
of antifungal therapy for fungal keratitis.5,9 While the results of
these studies have provided some evidence for best treatment
practices, a larger randomized, controlled trial is needed to provide definitive evidence for the best treatment practices for fungal
keratitis.
Therapeutic Exploratory Study for Mycotic Ulcer

Treatment Trial
In 2008, we completed a therapeutic exploratory study for a
larger clinical trial comparing clinical outcomes in patients with
smear-positive fungal keratitis treated with either topical voriconazole or topical natamycin.5 This study was a randomized,
double-masked, controlled trial, in which 120 patients were
randomized to receive either topical voriconazole or topical
natamycin, and to receive repeat scraping or not. The primary
outcome was best spectacle-corrected visual acuity at 3 months
from enrollment.
Overall, there was no significant difference in 3-month visual
acuity with topical voriconazole treatment compared to natamycin. In a subanalysis of patients who were able to read some
letters on the eye chart (acuity between 20/40 and 20/400), there
was a trend toward a 2-line benefit with topical voriconazole.
In addition, there was a trend toward scraping being associated
with worse clinical outcomes. While it had been thought that
rescraping of the cornea may be beneficial to help penetration of
antifungal medications, this trial demonstrated that there does
not seem to be a benefit with rescraping of the cornea in fungal
keratitis. This trial also provided some preliminary evidence that
the use of voriconazole may result in better visual outcomes in a
subset of patients, but this result must be confirmed in a larger,
confirmatory trial.
The Role of Antifungal Susceptibility on Clinical

Outcome
The role of antifungal susceptibility on clinical outcomes is not
clear for fungal keratitis. There is some evidence that in systemic
fungal infections, resistant fungal strains may have worse clinical
outcomes than susceptible strains.10 In ocular fungal infections,
reports indicate that minimum inhibitory concentration (MIC)
may be associated with clinical outcome.11 In a prespecified secondary analysis of the Mycotic Ulcer Treatment Trial therapeutic
exploratory study, we analyzed the association between MIC
and clinical outcome. We found that a higher MIC was associated with an increased likelihood of perforation, demonstrating that resistant strains of fungus lead to poor outcomes. This
emphasizes the need the development and study of new antifungal strategies.
Gender Differences in Healing Rates for Fungal

Keratitis
We also found that there appear to be gender differences in
re-epithelialization after a fungal corneal ulcer. Women re-epithelialized twice as slowly as men in a model controlling for age,
baseline epithelial defect size, and treatment arm. There may be
differences in re-epithelialization because of androgens mediating
the lacrimal and meibomian glands, and recently we have demonstrated that there are differences in the tear protein makeup
between men and women.12 Gender may play a role in determining clinical outcomes, and responses to treatment between men
and women may differ. Analyzing clinical responses in men and
women remains important in the study of fungal keratitis.
Future Directions
While the number of rigorous studies in fungal keratitis is
increasing, there is a need for larger sample size confirmatory
clinical trials. We are currently enrolling patients in 2 large
National Eye Institutefunded fungal corneal ulcer clinical trials.
The first is comparing topical voriconazole and topical natamycin in patients with enrollment visual acuity between 20/40 and
20/400. 368 patients are being enrolled in this trial. We are currently more than halfway done with enrollment. The second trial
is evaluating the addition of oral voriconazole in the treatment
of severe fungal keratitis. These patients have enrollment acuity of worse than 20/400, and 240 patients are being enrolled in
this trial. Patients are randomized to receive topical voriconazole
with oral voriconazole, or topical voriconazole with placebo.
Currently we are approximately 25% through with enrollment.
We expect the results of these trials not only to provide definitive
evidence on the use of natamycin and voriconazole, and the use
of an oral antifungal agent, but also to provide a large database
to answer a host of secondary questions in the treatment and
clinical response of fungal keratitis.
Cornea
29
References
1. Chowdhary A, Singh K. Spectrum of fungal keratitis in north India.
Cornea 2005; 24:8-15.
2. Laspina F, Samudio M, Cibils D, et al. Epidemiological characteristics of microbiological results on patients with infectious corneal
ulcers: a 13-year survey in Paraguay. Graefes Arch Clin Exp Ophthalmol. 2004; 242:204-209.
8. Lalitha P, Shapiro B, Srinivasan M, Prajna N, et al. Antimicrobial

susceptibility of Fusarium, Aspergillus, and other filamentous fungi
isolated from keratitis. Arch Ophthalmol. 2007; 125:789-793.
9. Prajna N, John R, Nirmalan P, Lalitha P, Srinivasan M. A randomized clinical trial comparing 2% econazole and 5% natamycin for
the treatment of fungal keratitis Br J Ophthalmol. 2003; 87:12351237.
3. Leck A, Thomas P, Hagan M, et al. Aetiology of suppurative corneal ulcers in Ghana and south India, and epidemiology of fungal
keratitis. Br J Ophthalmol. 2002; 86:1211-1215.
10. Rex J, Pfaller M. Has antifungal susceptibility testing come of age?

Clin Infect Dis. 2002; 35:982-989.
4. Srinivasan M, Gonzales C, George C, et al. Epidemiology and aetiological diagnosis of corneal ulceration in Madurai, south India. Br J
Ophthalmol. 1997; 81:965-971.
11. Shapiro B, Lalitha P, Loh A, Fothergill A, Prajna N, et al. Susceptibility testing and clinical outcome in fungal keratitis. Br J Ophthalmol. 2010; 94(3):384-385.
5. Prajna N, Mascarenhas J, Krishnan T, et al. Comparison of natamycin and voriconazole for the treatment of fungal keratitis. Arch
Ophthalmol. 2010; 128(6):672-678.
12. Ananthi S, Santhosh R, Nila M, Prajna N, Lalitha P, Dharmalingam K. Comparative proteomics of human male and female tears
by two-dimensional electrophoresis. Exp Eye Res. 2011; 92:454463.
6. Varaprasathan G, Miller K, Lietman T, et al. Trends in the etiology

of infectious corneal ulcers at the F.I. Proctor Foundation. Cornea
2004; 23:360-364.
7. Alfonso E, Cantu-Dibildox J, Munir W, et al. Insurgence of Fusarium keratitis associated with contact lens wear. Arch Ophthalmol.
2006; 124:E1-E7.
30
| Cornea
Corneal Collagen Crosslinking: Does It Have a Role in

Managing Infectious Keratitis?
The Athens Protocol: The Management of Keratoconus and Post-LASIK
Ectasia With Combined, Same-Day Partial Topography-Guided PRK and
Collagen Crosslinking
Cornea collagen crosslinking (CXL) has been well established to
halt the progression of ectasia and keratoconus (KCN). A second
procedure for visual rehabilitation may sometimes be needed
after CXL for treatment of progressive KCN or post-LASIK ectasia. Following many years of employing CXL for ectasia cases,
we introduced the Athens Protocol: same-day topographyguided partial PRK and CXL.
Figure 1. The basic steps of the Athens Protocol: Upper left, the PTK
treatment plan on the Alcon/WaveLight platform. Upper right, following
PTK, areas of the Bowman have been ablated by PTK, confirming evidence that the epithelium over the cone is thinner. Lower left, The treatment plan of the topography-guided partial PRK that is the core concept
of this platform. Lower right, MMC application prior to the riboflavin
and CXL.
Our scientific findings support the conclusion that simultaneous topography-guided partial PRK with CXL offers a safe and
effective approach for normalizing the cornea and enhancing
visual function in eyes with ectatic conditions. The core importance of combining CXL in this technique is that it addresses
highly irregular astigmatism in the management of eyes with
keratoconus and post-LASIK ectasia.
Our theoretical and clinical evidence supports the use of the

Athens protocol where CXL and topography-guided surface ablation are performed in the same session rather than sequentially.
It is our experience that surface ablation using the topography-guided excimer laser platform (Allegretto, Alcon/WaveLight) effectively and predictably normalizes the corneal surface
and improves functional vision, and we believe there is a synergistic effect when this procedure is performed simultaneously
with CXL.
Safety with our combination approach has been favorable as
well. Although postoperative haze and delayed epithelial healing
have occurred, these have been minor complications in a small
number of eyes within a very large series.
Figure 2. The clinical picture of the O.D. of a 27-year-old male with

advanced KCN. His preop BSCVA was 20/50 with -2.5, 5 @ 80. He
underwent the Athens Protocol and his UCVA is now 20/30; BSCVA is
20/20 with -1, -1.5 @ 85. The slitlamp photo shows the cornea clarity
and the ground-glass appearance typical of CXL.
Cornea
Meeting Visual Rehabilitation Needs
31
Results from a comparison of two large, consecutive series of

eyes treated at the same session or with CXL first followed 1 year
later by a topography-guided surface ablation showed statistically significant differences in a number of outcome parameters
favoring the same day procedure. The study, which has been
published (J Refract Surg. 2009; 25:S812-818), included 127
eyes in the sequential group and 198 eyes treated with the Athens
Protocol.
Figure 3. Cornea OCT of the same eye 7 months following the Athens
Protocol. One can appreciate the anterior cornea hyper-reflectivity consistent with CXL and the demarcation line at about 300 microns depth
depicting (as we have introduced and published) the depth of effective
CXL. Those clinicians familiar with these findings following CXL alone
they may appreciate the enhanced depth and diameter of the CXL effect
noted on OCT, supporting the advantage of the Athens Protocol.
Although the efficacy of CXL for stabilizing keratectasia is well

established and the procedure also causes some corneal flattening, significant residual astigmatism limiting contact lens wear
may be a persistent problem for some patients. This situation
creates an indication to perform the topography-guided partial
PRK. The ablation removes no more than 50 microns of stroma
and at most treats 2 to 2.5D of astigmatism and up to 1D of
myopia.
The protocol begins with a 6.5-mm phototherapeutic keratectomy (PTK) to remove 50 microns of epithelium. Then,
the topography-guided partial PRK is performed, followed by
mitomycin C application (0.02% for 20 seconds) and the CXL
procedure. The excimer laser ablation resembles part of a hyperopic treatment. It is performed using a 5.5-mm effective optical
zone and targets steepening of the area adjacent to the cone in an
attempt to regularize the corneal surface.
In discussing our rationale for performing the two procedures
simultaneously with the ablation first, we have reported data
showing that the corneal epithelium and Bowman membrane can
act as barriers to UVA light penetration into the stroma. As these
tissues are removed with the PTK/PRK procedure, it seems intuitive that the efficacy of the CXL procedure would be increased.
This concept is supported by clinical findings.
For example, in a patient who had CXL alone in one eye and
the Athens protocol in the other, inspection of OCT maps for
hyper-reflectivity, which we recently described as a sign of the
extent of crosslinking, shows the area of crosslinking is much
broader and denser in the latter eye.
We additionally introduced the theory that the PRK-treated
eye represents a better biomechanical model for performing the
CXL procedure. In theory, an eye with a more regularized surface as opposed to one where there is ongoing strain from IOP
and eye rubbing localized over the cone peak would be better
strengthened by CXL and more likely to remain stable after the
procedure.
We believe redistribution of corneal strain by remodeling
the cornea with the surface ablation is a significant factor in the
synergistic effect achieved when performing the two procedures
together. The simultaneous procedure also avoids removing
crosslinked cornea, which occurs when performing CXL first followed by the laser treatment.
Figure 4. Pentacam comparison of preop with 7-month postop, showing

the significant normalization of the cone, keratometric flattening, and
better symmetry.
CASE
A 57-year-old man had severe corneal blindness from scarring
at the age of 12 following firework explosion. Uncorrected
distance visual acuity (UDVA) was 20/400 O.U. in 2009; pinhole to 20/100 in the right and 20/70 in the left. There was no
improvement to his visual function with spectacle refraction or
soft contact lenses, and there was intolerance to gas-permeable
contact lenses. There was no possible endothelial cell count in the
right and 2000 cells/mm2 in the left eye. Slitlamp biomicroscopy
revealed a severe horizontal central corneal scar O.U. Dilated
fundus examination revealed no cataract, normal disc, macula
and retina vessels.
CDVA was 20/100 O.U. with refraction: +4.00, -4.50 @ 135
O.D. and O.S: +3.50, -1.00 @ 55. Respective keratometries were
42.3, 60.4 @ 17 and 35.8, 39.1 @ 151.3.
Tomographic evaluation (Oculyzer II, WaveLight, Erlagen,
Germany) showed thinnest pachymetry of 467m and 448m
O.D. and O.S., respectively. Considering the options of lamellar and penetrating keratoplasty, we discussed and employed
the Athens Protocol (combined topography-guided partial PRK
and CXL) O.D. in February 2010 and O.S. in September 2010.
We have previously reported on this technique1-5 for the management of cornea ectasia. The treatment planpivotal to the
application of the Athens Protocolcombines a myopic ablation over the elevated cornea and a partial hyperopic application peripheral to the flattened-by-scarring inferior cornea. This
combination treatment enhances the normalization of the severe
irregularity with small ablation (35m) over the thinnest cornea.
Fifteen months after the O.D. treatment, the cornea had cleared
and was topographically stable, with UDVA 20/50 and CDVA
20/40 and refraction +0.50, -2.00 @ 5. We noted a similar outcome 8 months after the O.S. treatment, with UDVA 20/50 and
CDVA 20/40, -0.50, -2.00 @ 170.
32
Patients tomographic keratometry O.D. has improved to

44.3, 59.0 @ 13.7 and O.S., 35.4, 38.4 @ 166.3 O.S. Endothelial
cell counts are 1600 cells/mm2 and 2010 cells/mm2, respectively.
The patient has recently obtained a drivers license and has
assumed a more independent lifestyle.
In this particular patient, the therapeutic aim of the topography-guided PRK was to normalize the corneal surface, and the
employment of the CXL was two-fold: to reduce corneal scarring
by eliminating keratocytes and to stabilize the thinner cornea
produced by the removal of corneal tissue with the therapeutic
topography-guided ablation.
We feel that the introduction of this successful management
of severe corneal abnormalities and scarring with the Athens
Protocol may provide an effective alternative to other surgical or
medical options.
| Cornea
References
1. Kanellopoulos AJ, Skouteris VS. Secondary ectasia due to forceps
injury at childbirth. management with combined topographyguided partial PRK and collagen cross-linking (the Athens Protocol), followed by the implantation of a phakic intraocular lens
(IOL). J Refract Surg. 2011. In print.
2. Kanellopoulos AJ, Binder PS. Management of corneal ectasia after
LASIK with combined, same-day, topography-guided partial transepithelial PRK and collagen cross-linking: the Athens Protocol.
JRefract Surg. 2011; 27(5):323-331.
3. Kruger RR, Kanellopoulos AJ. Stability of simultaneous topography-guided photorefractive keratectomy and riboflavin/UVA crosslinking for progressive keratoconus: case reports. J Refract Surg.
2010; 26(10):S827-832.
4. Kanellopoulos AJ. Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus. J Refract Surg. 2009; 25(9):S812-818.
5. Kanellopoulos AJ, Binder PS. Collagen cross-linking (CCL) with
sequential topography-guided PRK: a temporizing alternative for
keratoconus to penetrating keratoplasty. Cornea 2007; 26(7):891895.
LEGEND, Figure 1.
Image A: Slit lamp of the OD at presentation,
showing the significant horizontal cornea scar.
Image B: Slit lamp picture of the OS. The cornea scar similar to the OS.
Image C: The treatment plan on the Wavelight excimer platform for topography-guided
partial PRK employed for the OD treatment.
The treatment planpivotal to the application
of the Athens Protocolcombines a myopic
ablation over the elevated cornea and a partial
hyperopic application peripheral to the flattened by scarring inferior cornea. This combination treatment enhances the normalization
of the severe irregularity with small ablation
(35um) over the thinnest cornea.
Image D: Tomography maps (Oculyzer, Wavelight, Erlagen, Germany) of the OD and OS
pre-operative to the Athens Protocol.
Image E: Tomography maps of the OD and
OS post-operative to the Athens Protocol. 15
months following the OD and 8 months following the OS
Image F: Slit lamp Picture of the OD, 15
months following treatment, cornea regularity
and improvement in translucency is evident
(when compared to Image A).
Image G: Slit lamp Picture of the OS, 8 months
following treatment, cornea regularity and
improvement in translucency is evident (when
compared to image B).
Image H: The treatment plan on the Wavelight
excimer platform employed for topographyguided partial PRK of the OS.
Cornea
33
Now That We Have Topical Ganciclovir, What Is the

Role of Oral Antivirals?
Since the days of the ancient Egyptians, corneal epithelial
debridement has been used as a treatment option for herpes simplex virus (HSV) epithelial keratitis. Whereas the average healing time of an untreated HSV epithelial dendrite is 9-10 days,
treatment with debridement and patching reduces healing time
to 2.5 days.
Several thousand years later, topical antivirals were introduced for the treatment of HSV epithelial keratitis. The first of
these antivirals was idoxuridine, followed by vidarabine, trifluorothymidine, acyclovir, and most recently ganciclovir. The
healing time of HSV epithelial keratitis treated with any of these
topical antivirals is about 7 days. Over the years these agents
have also been widely used by ophthalmologists as part of therapeutic regimens for the treatment of HSV stromal disease and
iritis, but their role in the management of these immunologically
mediated diseases is not completely clear, and they are generally used as prophylaxis against recurrent infectious epithelial
disease in the face of treatment of the immunological disease
with topical corticosteroids. Over the years these antiviral agents
have also been widely used by ophthalmologists for prophylaxis
against recurrent infectious epithelial keratitis when treating
HSV stromal keratitis and iritis (immune-mediated diseases)
with a topical corticosteroid.
Despite the introduction of topical antivirals in the 1970s,
the rates of corneal transplantation for HSV keratitis remained
high until the 1990s, corresponding with the increased use of
oral acyclovir in the management of HSV ocular disease. The
average healing time of HSV epithelial keratitis treated with
oral acyclovir is also about 7 days. And in a landmark study
published in the New England Journal of Medicine as part of the
HEDS, investigators demonstrated that acyclovir prophylaxis
(400 mg PO b.i.d.) reduced overall recurrence rates of ocular

HSV by about 50%. Many clinicians have noted even lower
recurrence rates when patients were treated prophylactically
with higher doses of antivirals, and a recent retrospective study
carried out by the Mayo Clinic reported an 85%-95% reduction
in ocular HSV in patients receiving oral antiviral prophylaxis
(varying drugs and doses). Generic forms of oral acyclovir, valacyclovir, and famciclovir are all widely available. All 3 of these
drugs are easy to take, have a long shelf life, and are extremely
well tolerated, even when taken for years. After oral administration all 3 drugs also reach therapeutic levels in the tear film and
aqueous.
At this point topical ganciclovir has been approved by the
FDA for the treatment of HSV epithelial keratitis, and the clinical data suggest that it is non-inferior to topical acyclovir in
the treatment of this form of HSV ocular disease. There is no
published evidence at this time that topical ganciclovir is effective for the treatment of HSV stromal keratitis or iritis, or for
the prophylaxis of recurrent ocular disease. Topical ganciclovir
is more expensive than oral antiviral medications. It is preserved
with benzalkonium chloride, and anecdotal reports note that it
is better tolerated than trifluorothymidine, which is preserved
with thimerosal. Sixty percent of patients using topical ganciclovir report blurred vision, 20% report irritation, and 5% develop
punctate keratitis. At this point in time topical ganciclovir is a
reasonable alternative to the use of trifluorothymidine or oral
acyclovir for the treatment of HSV epithelial keratitis. However,
topical ganciclovir is significantly more expensive than oral
antivirals, and patients have more rapid healing times following
corneal debridement.
34
| Cornea
Perioperative Antibiotics: Looking for a Consensus

Amid the Chaos
Prophylaxis for Intraocular Surgery
Francis S Mah MD
Prophylactic strategies for intraocular surgery include using topical antibiotic eye drops before surgery, applying 5% povidone
iodine solution to the conjunctival cul-de-sac, preparing the periocular skin with 10% povidone iodine scrub, careful sterile draping of the eyelid margins and eyelashes, adding antibiotics to the
irrigating solution, injecting intracameral antibiotics at the close
of surgery, injecting subconjunctival antibiotics, collagen shield
mediated antibiotic delivery, and applying topical antibiotic eye
drops after surgery. A nonrandomized, controlled trial provided
evidence that using topical 5% povidone iodine solution in the
conjunctival cul-de-sac reduces the incidence of postoperative
infection.1,2
Lower concentrations of povidone iodine are less effective in
reducing conjunctival bacterial colony counts.3 Systemic antibiotics are rarely used; however, it has been shown that certain
fluoroquinolone antibiotics penetrate the blood/ocular barrier
adequately to reach levels above the minimum inhibitory concentrations for many organisms inside the eye.4-6
Although still controversial in the United States, there is some
evidence that supports the use of intraocular antibiotics to reduce
the risk of endophthalmitis. The European Society of Cataract
and Refractive Surgeons (ESCRS) study,7 a partially masked,
randomized, placebo-controlled multinational trial of the prophylactic effect of intracameral cefuroxime injection at the conclusion of the procedure and/or perioperative levofloxacin eye
drops on the incidence of endophthalmitis after phacoemulsification, was halted early because of results of a beneficial effect of
intracameral cefuroxime. With data from 13,698 patients with
complete follow-up records, investigators found that the odds
ratio for developing endophthalmitis was 4.59 (95% CI, 1.7412.08; P = .002) in the group not receiving intracameral injection
of cefuroxime, a second-generation cephalosporin. However, the
incidence of endophthalmitis in the control group was approximately 3 times higher than that reported in most other studies
from U.S. centers. This raises the question of whether the results
can be generalized to a U.S. population. It is important to note
that in the ESCRS prophylaxis study, all patients received preoperative povidone-iodine 5% solution in the conjunctival culde-sac, and a postoperative topical fluoroquinolone started 18
hours following the conclusion of surgery. It was felt that these
two maneuvers were standard of care surrounding cataract surgery. An earlier retrospective study in Sweden reported efficacy
of intracameral cefuroxime in reducing postcataract endophthalmitis.8 Two retrospective studies in Spain have reported that
intracameral injection of cefazolin, a first-generation cephalosporin, reduced postcataract endophthalmitis.9,10
Evidence of the benefit of injecting subconjunctival antibiotics
at the close of surgery is inconclusive and is associated with risks
that include intraocular toxicity with the potential for macular
infarction if aminoglycosides are used and inadvertently injected
into the eye.11 In the Cataract in the Adult Eye Preferred Practice
Pattern, the America Academy of Ophthalmology recommends
use of a 5% solution of povidone iodine in the conjunctival culde-sac to prevent infection. Given the absence of clear evidence
about the benefit of other prophylactic measures, the Academy
also notes that it is up to the ophthalmologist to decide on the
use of any particular strategy in addition to povidone iodine in
the perioperative period.12
Evidence-based recommendations and a review of the literature will be presented to allow participants all of the information
needed to develop reasonable strategies for prophylaxis.
References
1. Ciulla TA, Starr MB, Masket S. Bacterial endophthalmitis prophylaxis for cataract surgery: an evidence-based update. Ophthalmology 2002; 109:13-24.
2. Speaker MG, Menikoff JA. Prophylaxis of endophthalmitis with
topical povidone-iodine. Ophthalmology 1991; 98:1769-1775.
3. Ferguson AW, Scott JA, McGavigan J, et al. Comparison of 5%
povidone-iodine solution against 1% povidone-iodine solution in
preoperative cataract surgery antisepsis: a prospective randomised
double blind study. Br J Ophthalmol. 2003; 87:163-167.
4. Hariprasad SM, Shah GK, Mieler WF, et al. Vitreous and aqueous
penetration of orally administered moxifloxacin in humans. Arch
Ophthalmol. 2006; 124:178-182.
5. Kampougeris G, Antoniadou A, Kavouklis E, et al. Penetration of
moxifloxacin into the human aqueous humour after oral administration. Br J Ophthalmol. 2005; 89:628-631.
6. Garcia-Saenz MC, Arias-Puente A, Fresnadillo-Martinez MJ,
Carrasco-Font C. Human aqueous humor levels of oral ciprofloxacin, levofloxacin, and moxifloxacin. J Cataract Refract Surg. 2001;
27:1969-1974.
7. Barry P, Seal DV, Gettinby G, et al. ESCRS study of prophylaxis of
postoperative endophthalmitis after cataract surgery: preliminary
report of principal results from a European multicenter study.
JCataract Refract Surg. 2006; 32:407-410.
8. Montan PG, Wejde G, Koranyi G, Rylander M. Prophylactic intracameral cefuroxime: efficacy in preventing endophthalmitis after
cataract surgery. J Cataract Refract Surg. 2002; 28:977-981.
9. Garat M, Moser CL, Alonso-Tarres C, et al. Intracameral cefazolin
to prevent endophthalmitis in cataract surgery: 3-year retrospective
study. J Cataract Refract Surg. 2005; 31:2230-2234.
10. Romero P, Mendez I, Salvat M, et al. Intracameral cefazolin as
prophylaxis against endophthalmitis in cataract surgery. J Cataract
Refract Surg. 2006; 32:438-441.
11. Brown GC, Eagle RC, Shakin EP, et al. Retinal toxicity of intravitreal gentamicin. Arch Ophthalmol. 1990; 108:1740-1744.
12. American Academy of Ophthalmology. Cataract in the Adult Eye,
Preferred Practice Pattern. San Francisco: American Academy of
Ophthalmology, 2006. Available at: www.aao.org/ppp. Accessed
May 20, 2009
Cornea
Section III: Corneal Transplantation Lamellar Keratoplasty
35
A Decade of Endothelial Keratoplasty: What Has the

Literature Taught Us?
Mark A Terry MD
I. Endothelial keratoplasty (EK) has now replaced penetrating keratoplasty (PK) as the standard of care for
endothelial dysfunction.1
A. Eye Bank Association of America 2010 statistical
report shows EK to represent 45% of all transplants
performed in the United States.
B. Most common indication for EK in the United
States is Fuchs dystrophy.
C. EK can be performed in cases of pseudophakic
bullous keratopathy, ABK, congenital hereditary
endothelial dystrophy, iridocorneal endothelial
syndrome, and in the presence of anterior chamber
lenses, tubes, trabeculectomy blebs, etc.
II. Established Benefits of EK2-5
A. Better quality of vision than PK: Less aberrations,
smoother surface
B. Astigmatically neutral when a scleral incision is used
C. Induced refractive hyperopic shift that averages 1.0
to 1.5 Dlikely primarily from posterior curvature
changes of the hourglass donor
D. Stronger eye with substantial resistance to postoperative trauma
E. More predictable triple procedure than PK
III. Most Common Complications of EK4
A. Dislocation: Rates from 1% to 82% reported in literature.
3. Bubble size, bubble time, IOP pressure: Common

practice prejudices, but there is nothing in literature to support one method over another.
B. Iatrogenic primary graft failure11-14
1. Minimize endothelial trauma by minimizing
donor manipulations.
2. Use larger diameter wounds for insertion or use
tissue inserter.
C. Pupillary block glaucoma
1. Leave a small, freely mobile air bubble in eye at
end of surgery: Lowest rate of pupillary block,
highest rate of donor attachment.3,4
2. Place an inferior peripheral iridectomy/iridotomy: Not always effective15 and can result in
bleeding.
D. Eccentric donor trephination16,17
1. Can result in primary graft failure (PGF) and epithelial ingrowth to interface
2. Completely avoided by using the microscope to
trephinate donor tissue; never use the naked eye
to assess edge clearance within a tolerance of
only 0.25 mm.
V. Methods of Insertion: Benefits and Risks
A. Forceps insertion with taco folding: Most established method, most surgeon dependent3,4,7
B. Iatrogenic primary graft failure: Rates from 0% to

29% reported in literature.
B. Busin glide pull through: Popular but sparse literature data; appears similar to forceps insertion by
experienced surgeons18
C. Pupillary block glaucoma: Rates from 0.1% to

9.5% reported in literature.
C. Cartridge loaded pull through: Appears comparable

to forceps19
D. Eccentric donor trephination: Rates from 0% to

10% reported.
D. All others (sheets glide push in, Healon on sclera, or

sheets glide push in, pull in, etc.): No literature on
complication rates or endothelial survival20,21
IV. Methods of Avoiding Dislocation and other Complications6: Benefits and Risks
A. Dislocation
1. Minimize endothelial trauma by minimizing
donor manipulations
2. Evacuate interface fluid
a. Surface sweeping with IOP increased with air
filling chamber: Fully effective but epithelial
damage can occur.7
b. Venting full-thickness corneal incisions:
Effective, but eye is put at risk for postoperative epithelial ingrowth and infections in
interface, and late corneal melting.8-10
E. Tissue inserters (see below)

VI. Endothelial Survival After EK3,4,14,8,21-23
A. Worse than PK at 1 year; better than PK at 5 years
B. Technique dependent: Smaller incisions for insertion
cause more endothelial damage, higher dislocation
rates, and higher PGF rates.14,22,23
VII. Donor Tissue: Common knowledge is often wrong,
and the truth is . . .
A. Higher preoperative endothelial cell counts of a
donor do not yield higher postoperative cell counts
and do not protect against dislocation or primary
graft failure.24
36

B. Larger diameter donor discs that theoretically transplant more total endothelial cells do not result in
higher postoperative cell counts and do not protect
against dislocation or primary graft failure.25
C. Longer storage time of donor tissue does not result
in worse postoperative cell counts and does not
increase dislocation or PFG rates.26
D. The thickness of the donor tissue does not influence
the postoperative visual acuity level: thinner Descemet-stripping automated endothelial keratoplasty
(DSAEK) grafts do not yield better vision than
thicker grafts.27,28
VIII. DSAEK Tissue Inserters: Very Little Data Currently
Available in Literature29
A. Platform inserters: NCI and Endoserter
B. Glide inserters: Tan endoglide
C. Cartridge inserter: InJEk technique
IX. Descemet-Membrane Endothelial Keratoplasty
(DMEK) and Descemet Membrane Automated
Endothelial Keratoplasty (DMAEK)30-32
A. Better (and faster) visual acuities postop than
DSAEK
B. Steep learning curve
C. Higher rate of re-bubbling: 25% (DMAEK) to
60% (DMEK) in U.S. studies (5% in Melles recent
DMEK series)
D. Higher rate of primary graft failure: 5% to 8%
E. Higher rate of tissue wastage: 5% to 16%
References
Cornea
8. Price MO, Price FW. Endothelial cell loss after Descemet stripping
with endothelial keratoplasty: influencing factors and 2 year trend.
9. Bansal R, Ramasubramanian A, Das P, Sukhija J, Jain AK. Intracorneal epithelial ingrowth after Descemet stripping endothelial
keratoplasty and stromal puncture. Cornea 2009; 28(3):334-337.
10. Hannush SB, Chew HF, Eagle RC. Late-onset deep infectious keratitis after Descemet stripping endothelial keratoplasty with vent
incisions. Cornea 2011; 30:229-232.
11. Terry MA, Shamie N, Chen ES, Phillips PM, Hoar KL, Friend DJ.
Pre-cut tissue for Descemets stripping endothelial keratoplasty:
vision, astigmatism, and endothelial survival. Ophthalmology
2009; 116:248-256.
12. OBrien PD, Lake DB, Saw VP, Rostron CK, Dart JK, Allan BD.
Endothelial keratoplasty: case selection in the learning curve. Cornea 2008; 27:1114-1118.
13. Suh LH, Yoo SH, Deobhakta A, et al. Complications of Descemets
stripping with automated endothelial keratoplasty: survey of 118
eyes at one institute. Ophthalmology 2008; 115:1517-1524.
14. Foster JB, Vasan R, Walter KA. Three-millimeter incision Descemet stripping endothelial keratoplasty using sodium hyaluronate
(Healon): a survey of 105 eyes. Cornea 2011; 30:150-153.
15. Koenig SB, Covert DJ. Early results of small-incision Descemets
stripping and automated endothelial keratoplasty. Ophthalmology
2007; 114:221-226.
16. Oster SF, Ebrahimi KB, Eberhart CG, Schein OD, Stark WJ, Jun
AS. A clinicopathologic series of primary graft failure after Descemets stripping and automated endothelial keratoplasty. Ophthalmology 2009; 116:609-614.
17. Terry MA, Shamie N. Avoiding eccentric trephination [letter]. Ophthalmology 2009; 116:2481-2482.
18. Busin M, Bhatt PR, Scorcia V. A modified technique for Descemet
membrane stripping automated endothelial keratoplasty to minimize endothelial cell loss. Arch Ophthalmol. 2008; 126:1133-1137.
1. Medical Advisory Board, eds. Annual Statistical Report of the

EBAA. Washington, DC: Eye Bank Association of America; 2010.
19. Kaiserman I, Bahar I, McAllum P, Slomovic AR, Rootman DS.

Suture-assisted vs forceps-assisted insertion of the donor lenticula
during Descemet stripping automated endothelial keratoplasty. Am
J Ophthalmol. 2008; 145:986-990.
2. Terry MA. Endothelial keratoplasty: clinical outcomes in the two

years following deep lamellar endothelial keratoplasty (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc.
2007; 105: 530-563.
20. Balachandran C, Ham L, Birbal RS, Wong TH, van der Wees J,
Melles GR. Simple technique for graft insertion in Descemet-stripping (automated) endothelial keratoplasty using a 30-gauge needle.
J Cataract Refract Surg. 2009; 35(4):625-628.
3. Terry MA, Shamie N, Chen ES, et al. Endothelial keratoplasty for

Fuchs dystrophy with cataract: complications and clinical results
with the new triple procedure. Ophthalmology 2009; 116:631-639.
21. Price MO, Fairchild KM, Price DA, Price FW. Descemets stripping
endothelial keratoplasty: five year graft survival and endothelial cell
loss. Ophthalmology 2011; 118(4):725-729.
4. Lee WB, Jacobs DS, Musch DC, Kaufman SC, Reinhart WJ, Shtein
RM. Descemets stripping endothelial keratoplasty: safety and
outcomesa report by the American Academy of Ophthalmology.
Ophthalmology 2009; 116:1818-1830.
22. Terry MA, Saad HA, Shamie N, et al. Endothelial keratoplasty: the
influence of insertion techniques and incision size on donor endothelial survival. Cornea 2009; 28:24-31.
5. Jun B, Kuo AN, Afshari NA, Carlson AN, Kim T. Refractive

change after Descemet stripping automated endothelial keratoplasty
surgery and its correlation with graft thickness and diameter. Cornea 2009; 28(1):19-23.
6. Terry MA. Ten tips for successful DSAEK surgery. Tech Ophthalmol. 2011; 9(1):10-14.
7. Terry MA, Shamie N, Chen ES, Hoar KL, Friend DF. Endothelial
keratoplasty: a simplified technique to minimize graft dislocation,
iatrogenic graft failure and pupillary block. Ophthalmology 2008;
115:1179-1186.
23. Price MO, Bidros M, Gorovoy M, et al. Effect of incision width

on graft survival and endothelial cell loss after Descemet stripping
automated endothelial keratoplasty. Cornea 2010; 29:523-527.
24. Terry MA, Shamie N, Chen ES, Hoar KL, Phillips PM, Friend DJ.
Endothelial keratoplasty: the influence of pre-operative donor
endothelial densities on dislocations, primary graft failure, and one
year cell counts. Cornea 2008; 27:1131-1137.
25. Terry MA, Li J, Goshe J, Davis-Boozer D. Endothelial keratoplasty:
the relationship between donor tissue size and donor endothelial
survival. Ophthalmology. Epub before print 6 Jun 2011.
26. Terry MA, Shamie N, Straiko MD, Friend DJ, Davis-Boozer D.
Endothelial keratoplasty: the relationship between donor tissue
Cornea
storage time and donor endothelial survival. Ophthalmology 2011;

118:36-40.
27. Ahmed KA, McLaren JW, Baratz KH, et al. Host and graft thickness after Descemet stripping endothelial keratoplasty for Fuchs
endothelial dystrophy. Am J Ophthalmol. 2010; 150:490-497.
28. Nieuwendaal CP, van Velthoven ME, Biallosterski C, et al. Thickness measurements of donor posterior disks after Descemet stripping endothelial keratoplasty with anterior segment optical coherence tomography. Cornea 2009; 28:298-303.
29. Foster JB, Swan KR, Vasan RA, Greven MA, Walter KA. Small
incision DSAEK: a comparison of a small incision tissue injector
and forcep techniques. Cornea. In press.
30. Price MO, Giebel AW, Fairchild KM, Price FW. Descemets membrane endothelial keratoplasty: prospective multi-center study of
visual and refractive outcomes and endothelial survival. Ophthalmology 2009; 116:2361-2368.
31. Ham L, Dapena I, van der Wees J, Melles GRJ. Endothelial cell
density after Descemet membrane endothelial keratoplasty: 1- to
3-year follow-up. Am J Ophthalmol. 2010; 149(6):1016-1017.
32. McCauley MB, Price MO, Fairchild KM, Price DA, Price FW Jr.
Prospective study of visual outcomes and endothelial survival with
Descemet membrane automated endothelial keratoplasty. Cornea
2011; 30(3):315-319.
37
38
Cornea
Ten Tips to Avoid Trouble When Transitioning to

Descemet-Stripping Endothelial Keratoplasty
Friedrich E Kruse MD FEBO, Bjrn Bachmann MD FEBO, Kathrin Laaser MD FEBO,
Ursula Schltzer-Schrehardt PhD, Claus Cursiefen MD FEBO
1. Select an appropriate patient.
Patient selection is of utmost importance for all variants of
Descemet-stripping endothelial keratoplasty. The success of the
procedure is largely dependent on the amount of endothelial cells
that are lost during insertion, unfolding, and attachment of the
graft. Endothelial loss is dependent on the ease of the manipulation of the donor tissue in the anterior chamber, which is influenced by two factors: the dimensions of the anterior chamber
and the pressure in the eye during surgery (vis a tergo). While a
soft eye is easiest to maintain during general surgery, the dimensions of the anterior chamber need to be taken into account during patient selection:
The beginning surgeon should seek to operate patients with:
r
r
r
r
%FFQBOUFSJPSDIBNCFS
&NFUSPQJBPSNZPQJB
1TFVEPQIBLJB XJUIVOFWFOUGVMIJTUPSZ
/PSNBMPSTMJHIUMZMBSHFSDPSOFBMEJBNFUFS
The beginning surgeon should not operate on patients with:

r 4IBMMPXBOUFSJPSDIBNCFS
r 4JHOJGJDBOUIZQFSPQJB
r 5IJDLDSZTUBMMJOFMFOT
Furthermore, all situations that impair the stability of the
iris diaphragm should be avoided initially because the use of air
bubbles required for unfolding the graft is greatly impaired in
situations such as:
r "QIBDJB
r 4UBUVTQPTUWJUSFDUPNZ
r -BSHFJSJTEFGFDUT
Since the ease of the removal of the patients Descemet membrane depends on the underlying pathology, we would suggest
to start with patients with Fuchs dystrophy before moving to
patients with pseudophakic bullous keratopathy and finally to
patients with keratopathy after 5-fluorouracil treatment or graft
dysfunction due to endothelial decompensation.
2. Select appropriate donor.

Experience with DSAEK has shown that both tissue from cold
storage (4C) and organ culture can be used and that younger
donors may have an advantage because of higher cell counts.
In DMEK donors under 60 years of age have proven to be not
suitable because of the increased elasticity of the Descemet membrane. Thus Descemet membranes from younger donors are difficult to unroll. In addition organ-cultured donor tissue seems to
have a slight advantage concerning graft adhesion.
3. Gain initial experience with Descemet-stripping

automated endothelial keratoplasty (DSAEK).
To gain experience with removal of the recipients Descemet
membrane as well as insertion and manipulation of a lamellar
graft, it seems to be best to start with DASEK. This technique

is in widespread use and offers the advantage of an established
surgery with a step-wise surgical approach and renders excellent
visual results.
Removal of the Descemet membrane, which might not be
necessary in all cases, may be performed under fluid or viscoelastic, however the use of air facilitates the visualization of small
remnants of Descemet membrane and therefore aids complete
removal of donor tissue.
Donor preparation should be performed by use of a microkeratome whenever possible because of the optical properties of
the resultant graft lenticule. Price and co-workers have shown
that the use of manually dissected grafts can also render excellent
visual results and that the use of precut tissue might be superior
to the use of manually dissected grafts.2 The use of precut tissue
is suggested for the beginning surgeon because it eliminates technical problems associated with microkeratome handling as well
as investment in costly equipment.
4. Select an appropriate injection technique for

DSAEK grafts.
In all forms of posterior lamellar surgery, the endothelial cell loss
during surgery is largely determined by the insertion technique.
In DSAEK there are 3 types of insertion techniques:
1. Forceps: Folding the graft like a taco with 60/40 overfold, trifold, 40/60 underfold
2. Glides: Busin glide, Sheets glide, Tan Endoglide
3. Inserters: Mechanical, closed chamber injector systems
with a variety of mechanisms
Although the use of the taco technique may render excellent
results in the hands of a very experienced surgeon, it is generally
agreed that the use of a glide or a inserter reduces endothelial
cell loss.3 For the beginning surgeon the use of a glide is highly
recommended: both the Busin glide4 and the Tan Endoglide,5 as
well as other devices on the market, may be used with very good
success.
5. Convert to Descemet membrane endothelial

keratoplasty (DMEK) or ultrathin DSAEK.
Although results with DSAEK are very good and tend to improve
over time, DMEK, developed by Melles, renders still better visual
acuity, which might be due to the unsurpassed quality of the posterior corneal surface resulting from this technique.1,6 Similarly,
ultrathin DSAEK using donor tissue of less than 100 m thickness renders favorable results. Until now problems with donor
preparation leading to tissue loss, problems manipulating the isolated Descemet membrane, and a lack of standardization of the
procedure, as well as the need for rebubbling, have precluded the
widespread use of this technique. We will therefore offer 4 steps
to avoid trouble with DMEK:
Cornea
39
6. Donor Preparation for DMEK With Minimal

Tissue Loss
In contrast to DSAEK, where preparation is based on a microkeratome cut, preparation of Descemet membrane in DMEK
does not require special instrumentation. The fundamental
problem is to gain access to the margin of the membrane and to
remove it without creating tears. The latter problem is addressed
by the recent development of a 2-forceps approach, which
reduces the tension exerted on a particular stretch of Descemet
membrane while pulling it apart from the underlying stoma.7
Also the surgeon or eye bank technician has to apply the same
principles as during capsulorrhexis by creating an outer margin
of the membrane that is free of tears. The principle of this technique is explained in a recent publication in the journal Cornea.7
The reader is referred to this article for details of preparation as
well as practical hints. In essence the technique consists of the
following steps:
r 3FNPWBMPGBTNBMM DVSWJMJOFBSTUSJQPG%FTDFNFUNFNbrane in the periphery of the corneoscleral button by very
careful use of a razor blade, which is used to drag Descemet membrane rather than to cut it
r -JGUJOHUIFDFOUSBMFEHFPG%FTDFNFUNFNCSBOFCZDBSFGVM
undermining with round blade
r 4VCUPUBMSFNPWBMPG%FTDFNFUNFNCSBOFCZTJNVMUBOFPVT
pulling with two forceps (The use of two forceps reduces
tension on the margin.)
r 5SFQIJOBUJPOXJUIBNNUSFQIJOF
r 4UBJOJOHXJUI5SZQBOCMVFBOEDPNQMFUFSFNPWBM
In our hands this technique enabled the successful removal of
392 of 400 preparations. In 1%-2% of donor corneal buttons,
central invaginations of Descemet membrane preclude complete
removal (see Tip #8 for further details of the anatomy of the
cleavage plane).
7. Control graft orientation in DMEK.

Upon release from the corneal stroma, the Descemet membrane
forms a roll with endothelial cells on the outside. Trypan blue
applied to the isolated roll for 1 minute can help to visualize the
roll in the anterior chamber. However, a surgeon who is transitioning to endothelial keratoplasty might have difficulties in
maintaining orientation in the anterior chamber. Indeed, even
gifted surgeons have reported on inverted grafts resulting in
graft failure. We have therefore suggested a very easy technique
to ensure orientation of DMEK grafts.9 This technique is based
on 3 circular marks, which are set in an identifiable order at the
outer margin of the graft by use of a 1-mm trephine (see Figure
1). This technique allows complete control over the orientation
of the graft.
8. Control graft insertion in DMEK.

There are several suggestions for how to insert a Descemet roll
into the anterior chamber. Melles and co-workers suggest using a
glass pipette, which implies loss of control over the orientation of
the graft during injection.10 Along with Price and co-workers,11
we1,7 prefer an IOL shooter. The use of a small air bubble inside
the Descemet roll offers additional stability because it precludes
lateral movement of the graft. Thus a reproducible insertion
becomes possible.
Figure 1.
9. Control donor unfolding and attachment in DMEK.

Unfolding of Descemet membrane in the anterior chamber
proves to be the most critical step in DMEK. Prolonged manipulation in the anterior chamber leads to loss of endothelial cells.
According to our experience,7 unfolding of the graft is made
relatively easy by using a small air bubble inside the Descemet
roll. In conjunction with the maneuver of controlled graft insertion, the roll can be delivered into the anterior chamber with the
air bubble already inside the roll. Thus the surgeon should aim at
injecting the roll in the right direction with an air bubble already
in place. Unfolding of the graft is achieved by lateral movement
of the air bubble and simultaneous enlargement of the bubble.
When the graft is unfolded and centered, the bubble is removed
while the anterior chamber becomes shallow. Now a bubble is
placed underneath the graft and the anterior chamber is filled
with air. We recommend filling the anterior chamber with air for
60 minutes and removing 50% of the air at the end of the first
hour.
10. Rebubbling: Compliance

While DMEK renders unsurpassed visual results along with fast
visual recovery, the procedure requires excellent and faithful
interaction between the surgeon and the patient. The patient has
to spend the first 2 days in bed looking at the ceiling. Thereafter graft detachment might occur, requiring rebubbling. Thus
more exact knowledge of the procedure on the patients side is
required than with any other type of corneal surgery. At present,
rebubbling is more frequent in DMEK than in DSAEK surgery;
however, the rate of graft detachment is significantly reduced by
the advent of improved insertion techniques (see above).
Selected Readings
1. Laaser K, Bachmann BO, Horn FK, et al. Donor tissue culture conditions and outcome after Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2011; 151(6):1007-1018.
2. Price MO, Price FW Jr. Descemets stripping with endothelial
keratoplasty: comparative outcomes with microkeratome-dissected
40

and manually dissected donor tissue. Ophthalmology 2006;
113(11):1936-1942.
3. Lee WB, Jacobs DS, Musch DC, et al. Descemets stripping endothelial keratoplasty: safety and outcomes: a report by the American
Academy of Ophthalmology. Ophthalmology 2009; 116(9):18181830.
4. Bahar I, Kaiserman I, Sansanayudh W, et al. Busin guide vs forceps for the insertion of the donor lenticule in Descemet stripping
automated endothelial keratoplasty. Am J Ophthalmol. 2009;
147(2):220-226.
5. Khor WB, Mehta JS, Tan DT. Descemet stripping automated endothelial keratoplasty with a graft insertion device: surgical technique
and early clinical results. Am J Ophthalmol. 2011; 151(2):223-232.
6. Ham L, Balachandran C, Verschoor CA, et al. Visual rehabilitation
rate after isolated Descemet membrane transplantation: Descemet
membrane endothelial keratoplasty. Arch Ophthalmol. 2009;
127(3):252-255.
7. Kruse FE, Laaser K, Cursiefen C, et al. A stepwise approach to
donor preparation and insertion increases safety and outcome
of Descemet membrane endothelial keratoplasty. Cornea 2011;
30(5):580-587.
8. Schltzer-Schrehardt U, Bachmann BO, Laaser K, Cursiefen C,
Kruse FE. Characterization of the Cleavage plane in Descemets
membrane endothelial keratoplasty. Ophthalmology. E-pub before
print 25 June 2011.
9. Bachmann BO, Laaser K, Cursiefen C, Kruse FE. A method to confirm correct orientation of Descemet membrane during Descemet
membrane endothelial keratoplasty. Am J Ophthalmol. 2010;
149(6):922-925.
10. Dapena I, Moutsouris K, Droutsas K, Ham L, van Dijk K, Melles
GR. Standardized no-touch technique for Descemet membrane
endothelial keratoplasty Arch Ophthalmol. 2011; 129(1):88-94.
11. Price MO, Giebel AW, Fairchild KM, Price FW Jr. Descemets
membrane endothelial keratoplasty: prospective multicenter study
of visual and refractive outcomes and endothelial survival. Ophthalmology 2009; 116(12):2361-2368.
Cornea
Cornea
Extreme Descemet-Stripping Automated Endothelial

Keratoplasty: When You Think DSEK Is the Best
Option for the Cornea, but Not for Your Coronaries
I. Feeling Detached? Attachment Issues
A. Tubing
B. Pressure
C. Aphakia
D. Posture
E. Dementia
F. Technique
1. Retention suture technique
2. Parallel and cloverleaf technique
II. Short on Space?
A. Anterior chamber (AC) IOLs
B. Hyperopia/shallow AC
III. Feel Like Youve Been Scarred? Do you need the whole
thing?
IV. Im Gonna Cut You: Eccentric Cuts and Recuts
V. This Will Make You Flip: Disk Inversion
41
42
Cornea
Descemet Membrane Endothelial Keratoplasty: Is It

Time for You to Convert From Descemet-Stripping
Endothelial Keratoplasty?
To make this decision you need to ask 3 relevant questions:
1. Does the thickness of an endothelial keratoplasty (EK)
graft affect vision?
2. Does the thickness of an EK graft affect the refractive
results?
3. Currently what is the thinnest EK donor graft?
Current evidence shows that very thin EK grafts provide better visual results and fewer refractive surprises.1-3 Currently the
thinnest EK graft available is Descemet membrane endothelial
keratoplasty (DMEK), consisting of only endothelium and the
Descemet membrane. DMEK donor grafts will be the thinnest
grafts available until we are able to transplant just endothelial
cells or do away with the need for donor tissue by stimulating the
patients own endothelial cells to regenerate. Work is being done
in these areas, but I suspect it will be a number of years before
they become available.
Currently no eye bank in the world that I know of screens
donor corneas for the curvature or Ks. Both living recipients and
donors all have a range of Ks from the mid-30s to low 50s. The
most common Ks in the typical bell-shaped curve will be in the
mid-40s, and usually when we place a donor EK graft there is
only mild folding of the tissue that occurs to allow it to conform
to the posterior surface of the recipient cornea. Bear in mind
that even if the donor and recipient Ks are the same, there will
still be some folding that has to take place when the donor graft
is placed on the recipient because we are inherently decreasing
the radius of curvature of the inner posterior surface as we add
thickness to the patients cornea with the graft. The degree of
folding and distortion of the donor tissue increases as the thickness of the donor tissue increases.4 The folding of the corneal
lamellae and gross distortion of the surfaces of the donor tissue
lead to degradation of the optics of the cornea, leading to poorer
vision and visual quality.5
Compared to penetrating keratoplasty (PK), Descemetstripping endothelial keratoplasty (DSEK) surgery represented
a dramatic improvement in visual results and safety for patients
because it eliminated the irregular astigmatism induced by
imperfectly aligning the anterior surfaces of the donor and recipient corneas with sutures as well as the need for a full-thickness
360-degree corneal incision. DMEK further helps eliminate the
induction of higher-order aberrations that have been shown to
occur in DSEK surgery.6
Why do we have less than perfect vision after EK? Why
doesnt everyone see 20/20? Some eyes have irregularities on
the anterior surface or subepithelial haze as a result of the prior
corneal edema, especially if bullous changes have occurred. That
is common to all EK, and I will not discuss this further as treatment of those issues improves the visual results for all types of
EK. However, in same-center studies like ours and those of Gerritt Melles, why has DMEK led to dramatic improvements in
the rates of 20/20 and 20/25 vision compared to DSEK cases?1-3
Looking at same-center studies is very important as they would

be expected to use the same methods of measuring visual acuity
and same criteria for excluding cases with poor visual potential
such as macular degeneration, amblyopia, etc. The induction of
higher-order aberrations and irregular astigmatism from the posterior surface of the cornea is the cause of poorer vision in DSEK.
Lets look at what we know about the induction of lowerorder aberrations in DSEK. BJ Dupps et al showed very nicely
that the variable thickness from center to periphery in the donor
tissue explains much of the hyperopic shift in DSEK eyes.7 They
also showed that thicker donor tissue caused more induced
hyperopia. However, what is rarely discussed is that microkeratomes do not cut a planar dissection. The Moria CB is an ideal
microkeratome for DSEK because it cuts thicker in the periphery
than the center and helps to offset the normal thickness gradient increase present in most corneas from center to periphery.
However, even that microkeratome does not cut uniformly at the
same thickness from one side to the other. Any irregularity in the
microkeratome cut induces some low- or higher-order aberration
to the optical system when the donor is placed in the eye. The
thinner the graft, the less chance of inducing these aberrations, so
why not just get rid of the stroma altogether?
What we dont know is whether leaving just 50 to 75 microns
of stromal tissue with DSEK will provide vision comparable to
that provided by DMEK. This is an area we are investigating.
I will also add that so far there have been no published reports
showing good visual results with any femtosecond laser for
DSEK. All of these lasers tend to produce a reasonably good surface appearance by electron microscopy but poor visual results
due to gross irregularities in the tissue induced by the compression of the cornea during applanation or an inability of the laser
to provide smooth cuts through the posterior portion of the
cornea, where the collagen lamellae are less dense than in the
anterior cornea.
The final hurdle for most surgeons performing DMEK is the
increased difficulty in doing the surgery and in the postoperative
care. I began my ophthalmology training in 1978. At that time,
all the cataracts at my university were performed as intra-caps.
We began doing extra-caps while I was a resident. I learned
phaco on my own after going into practice. Each of these steps
was hard, and I noticed that with each increase in surgical complexity, some surgeons would simply stop doing cataract surgery.
I also vividly recall a doctor in our town who openly told everyone he would not start using an operating microscope because he
got good results with his loops. (He was also the one who told
everyone to stand firm and not sign up with an HMO but on the
side contracted the whole job for himself.) Be careful of those
who say you should not do something because it is hard and not
worth the effort. Use your own deductive reasoning to look at
the results and the methods, and decide what is best for you and
best for your patients!
Cornea
References
1. Ham L, Balachandran C, Verschoor CA, van der Wees J, Melles
GRJ. Visual rehabilitation rate after isolated Descemet membrane
transplantation. Arch Ophthalmol. 2009; 127:252-255.
2. Price MO, Giebel AW, Fairchild KM, Price FW. Descemet membrane endothelial keratoplasty: prospective multicenter study of
visual and refractive outcomes and endothelial survival. Ophthalmology 2009; 116:2361-2368.
3. McCauley MB, Price MO, Fairchild KM, Price DA, Price FW.
Prospective study of visual outcomes and endothelial survival after
Descemet stripping automated endothelial keratoplasty. Cornea
2011; 30:315-319.
4. Patel SV, va der Meulen IJ, van den Berg TJ, McLaren JW. Quality
of vision in Fuchs endothelial dystrophy before and after Descemetstripping endothelial keratoplasty. Program and abstracts of the
Association for Research in Vision and Ophthalmology (ARVO);
May 2, 2011; Ft. Lauderdale, Florida.
5. Letko E, Price DA, Lindoso EM, Price MO, Price FW. Secondary
graft failure and repeat endothelial keratoplasty after Descemet
stripping automated endothelial keratoplasty (DSAEK). Ophthalmology 2011; 118:310-314.
6. Chamberlain W, Omid N, Lin A, Farid M, Gaster RN, Steinert RF.
Comparison of corneal surface higher-order aberrations after endothelial keratoplasty, femtosecond laser-assisted keratoplasty, and
conventional penetrating keratoplasty. Cornea. In press.
7. Dupps WJ, Qian Y, Meisler DM. Multivariate model of refractive
shift in Descemet-stripping automated endothelial keratoplasty.
JCataract Refract Surg. 2008; 34:578-584.
43
44
Cornea
Deep Anterior Lamellar Keratoplasty: Is It Time for

You to Convert From PK?
Rudy MMA Nuijts MD, Yanny YY Cheng MD, and the Dutch Lamellar Corneal Transplantation Study
(DLCTS) Group
Introduction
Deep anterior lamellar keratoplasty (DALK) can be performed
in patients with corneal stroma pathologies not affecting the
endothelium. Main advantages of DALK are prevention of longterm endothelial cell (EC) loss and reduction of immunological
rejection.
Visual outcomes of DALK might be limited compared to PK
if baring of the Descemet membrane is incomplete and interface
haze occurs. Deep dissection at the level of the Descemet membrane is thought to lead to better visual outcomes due to the
absence of stromal scarring at the graft-host stromal interface.1,2
Various techniques have been used to accomplish baring of the
Descemet membrane, and Anwar and Teichmann introduced
the so-called big-bubble technique, in which partial thickness
trephination is followed by stromal air injection to form an air
bubble to dissect the Descemet membrane from the posterior
stroma.3 This facilitates a safer exposure of the Descemet membrane and produces a smooth surface for high-quality vision (see
Figure 1). However, this big-bubble technique is technically challenging and may result in perforations of the Descemet membrane
in up to 57% of the cases.4 Recently, the Dutch Lamellar Corneal
Transplantation Study (DLCTS) was designed as a randomized,
controlled trial (RCT) to compare EC loss, visual and refractive
outcomes, quality of vision and complication profile after DALK
and PK.5 The outcomes of this study can probably answer the
question: DALK: Is It Time for You to Convert From PK?
0.31 0.3 logMAR in PK. This indicates that Anwars bigbubble technique achieves a deep dissection up to the level of the
Descemet membrane and does not lead to substantial interface
hazing. Although a significantly better BCVA following DALK
has been reported,4 the majority of the studies report similar values in DALK eyes, compared to PK eyes.6-11
Figure 2.
Refractive astigmatism values after DALK were comparable

to PK with an average refractive astigmatism of -3.37 D and
-3.76 D, respectively, after 12 months follow-up. This is in comparison with previous studies.6-11
The high preoperative topographic astigmatism values in both
the DALK and PK eyes (6.61 4.9 D and 6.90 6.4 D, respectively) may be caused by corneal irregularities due to epithelial
irregularities, corneal scars or keratoconus. Postoperative topographic astigmatism in the DALK group did not differ from the
PK group. Another study has shown similar astigmatism in both
groups after suture removal.2
Endothelial Cell (EC) Loss
Figure 1.
Visual and Refractive Outcomes After DALK and PK

Initial postoperative visual outcomes were significantly better in
the PK group, compared to the DALK group. However, 6 to 12
months after surgery, both the UCVA and BSCVA in the DALK
group reached the same level as in the PK group (see Figure 2).
BSCVA at 12 months was 0.39 0.3 logMAR in DALK and
EC loss was significantly higher following PK, compared to

DALK procedures performed without perforation of the Descemet membrane (12 months: 27.7 11.1% vs. 12.9 17.6%).
Three months after DALK surgery, EC loss was 6.6%, compared
to the preoperative situation. Surgically induced EC loss in
DALK treated eyes has been reported to be around 10%.12 Other
studies show an EC loss ranging from 6% to 20% in the first
year after DALK surgery.13-15 Shimazaki et al performed a RCT
comparing DALK and PK and found a stabilization of EC loss 6
months after a DALK procedure.16 Longer follow-up RCTs are
needed to evaluate this further.
A sufficiently high ECD is one of the major factors contributing to long-term graft survival. The higher EC loss in PK treated
eyes is in accordance with previous studies. A large cohort study
Cornea
with a 15-year follow-up showed that the endothelial cell density continues to decrease following a PK, until it stabilizes about
10 years after surgery.17 At this time, total EC loss is estimated
at 70%.
Complications
The main complication of a DALK procedure is intraoperative
perforation of the Descemet membrane. A recent overview of
comparable deep-dissection techniques reports a perforation
rate ranging from 6% to 57%.4,18 However, the reported perforation rates also depend on whether discrimination is made
between microperforations and larger perforations that require
a conversion. In the DLCTS a total perforation (microperforations and larger perforations) rate of 32% was noted, and 18%
of the patients required conversion to PK. This might be partially
explained by a learning curve of the surgeons. An additional
explanation is that 6 out of 9 patients with Descemet membrane
perforations in our study had been diagnosed with severe stromal scarring due to herpes simplex virus keratitis. We advise
caution when using the big bubble technique in eyes with stromal scarring.
In the DLCTS endothelial rejection occurred in 3 PK patients,
but did not occur in any DALK patient.
Cost-Effectiveness
The DLCTS also showed that DALK is more costly and more
effective than PK.19 Results on the National Eye Institute Visual
Function Questionnaire (NEI-VFQ 25) were in favor of DALK,
and endothelial cell loss in DALK patients remained stable
after 6 months postoperatively, whereas cell loss in PK patients
continued. Furthermore, it is shown that DALK procedures
performed without perforation of the Descemet membrane were
more effective. However, as it is unknown what society is willing
to pay for an additional improved patient, cost-effectiveness of
DALK within a limited follow-up period of 12 months is unclear.
In addition, the cost-effectiveness of DALK may improve over
time due to lower graft failure.
Conclusion
DALK procedures performed without perforation of the Descemet membrane result in a significantly lower EC loss, while
at the same time achieving equally good visual outcomes as a
PK procedure. Therefore, in 2 of 3 patients a DALK procedure
is highly beneficial for the patient since the host endothelium is
saved. However, in the occurrence of intraoperative perforation
of Descemet membrane this advantage is lost. Since complete
suture removal in the DLCTS was only performed in the minority of DALK and PK patients, a final comparison in postoperative visual outcomes, astigmatism differences, and suture-related
problems will only be possible after all sutures have been
removed. Given the obvious endothelium saving advantages
of DALK we believe it is time to convert. However, surgical
improvements are needed to standardize the big-bubble technique in order to reduce the perforation rate.
References
1. Sugita J, Kondo J. Deep lamellar keratoplasty with complete
removal of pathological stroma for vision improvement. Br J Ophthalmol. 1997; 81:184-188.
45
2. Ardjomand N, Hau S, McAlister JC, et al. Quality of vision and

graft thickness in deep anterior lamellar and penetrating corneal
allografts. Am J Ophthalmol. 2007; 143:228-235.
3. Anwar M, Teichmann KD. Big-bubble technique to bare Descemets membrane in anterior lamellar keratoplasty. J Cataract
Refract Surg. 2002; 28:398-403.
4. Anshu A, Parthasarathy A, Mehta JS, et al. Outcomes of therapeutic deep lamellar keratoplasty and penetrating keratoplasty for
advanced infectious keratitis: a comparative study. Ophthalmology
2009; 116:615-623.
5. Cheng YY, Visser N, Schouten JS, Wijdh RJ, Pels E, van Cleynenbreugel H, Eggink CA, Zaal MJ, Rijneveld WJ, Nuijts RM. Endothelial cell loss and visual outcome of deep anterior lamellar keratoplasty versus penetrating keratoplasty: a randomized multicenter
clinical trial. Ophthalmology 2011; 118:302-309.
6. Panda A, Bageshwar LM, Ray M, et al. Deep lamellar keratoplasty
versus penetrating keratoplasty for corneal lesions. Cornea 1999;
18:172-175.
7. Shimazaki J, Shimmura S, Ishioka M, Tsubota K. Randomized clinical trial of deep lamellar keratoplasty vs penetrating keratoplasty.
Am J Ophthalmol. 2002; 134:159-165.
8. Bahar I, Kaiserman I, Srinivasan S, et al. Comparison of three different techniques of corneal transplantation for keratoconus. Am J
Ophthalmol. 2008; 146:905-912 e1.
9. Krumeich JH, Knulle A, Krumeich BM. [Deep anterior lamellar
(DALK) vs. penetrating keratoplasty (PKP): a clinical and statistical
analysis]. Klin Monatsbl Augenheilkd. 2008; 225:637-648.
10. Watson SL, Ramsay A, Dart JK, et al. Comparison of deep lamellar
keratoplasty and penetrating keratoplasty in patients with keratoconus. Ophthalmology 2004; 111:1676-1682.
11. Han DC, Mehta JS, Por YM, et al. Comparison of outcomes of
lamellar keratoplasty and penetrating keratoplasty in keratoconus.
Am J Ophthalmol. 2009; 148:744-751 e1.
12. van Dooren BT, Mulder PG, Nieuwendaal CP, et al. Endothelial
cell density after deep anterior lamellar keratoplasty (Melles technique). Am J Ophthalmol. 2004; 137:397-400.
13. Fontana L, Parente G, Tassinari G. Clinical outcomes after deep
anterior lamellar keratoplasty using the big-bubble technique in
patients with keratoconus. Am J Ophthalmol. 2007; 143:117-124.
14. Morris E, Kirwan JF, Sujatha S, Rostron CK. Corneal endothelial
specular microscopy following deep lamellar keratoplasty with
lyophilised tissue. Eye 1998; 12(pt 4):619-622.
15. Bahar I, Kaiserman I, Srinivasan S, et al. Comparison of three different techniques of corneal transplantation for keratoconus. Am J
Ophthalmol. 2008; 146:905-912 e1.
16. Shimazaki J, Shimmura S, Ishioka M, Tsubota K. Randomized clinical trial of deep lamellar keratoplasty vs penetrating keratoplasty.
Am J Ophthalmol. 2002; 134:159-165.
17. Patel SV, Hodge DO, Bourne WM. Corneal endothelium and postoperative outcomes 15 years after penetrating keratoplasty. Am J
Ophthalmol. 2005; 139:311-319.
18. Reinhart WJ, Musch DC, Jacobs DS, Lee WB, Kaufman SC, Shtein
RM. Deep anterior lamellar keratoplasty as an alternative to penetrating keratoplasty a report by the American Academy of Ophthalmology. Ophthalmology 2011; 118(1):209-218.
19. van den Biggelaar FJ, Cheng YY, Nuijts RM, et al. Economic evaluation of deep anterior lamellar keratoplasty versus penetrating keratoplasty in The Netherlands. Am J Ophthalmol. 2011; 151:449459.
46
Cornea
Deep Anterior Lamellar Keratoplasty: Tips for the

Transitioning Surgeon
Geoffrey Tabin MD
I. Converting to Deep Anterior Lamellar Keratoplasty
A. Equal results to PKP but preserves patients endothelium
B. DALK procedures: Big bubble or manual dissection
II. Big Bubble: Anwar and Beyond
A. Getting started: Try for all cases with anterior
pathology; you can always convert.
B. Step-by-step big bubble DALK by video
C. Getting the big bubble tips and tricks: central 8-mm
trephination to 2/3 depth, remove anterior stroma
D. Use rounded cannula, deep dissection; air follows
path of least resistance; use 5 cc syringe.
E. Gentle pressure, past initial resistance until you see
stromal air expand to silvery round big bubble of
Descemet separation
F. Confirming the bubble and tricks for opening, use
viscoelastic
G. Safe dissection; decompress eye, cut into quadrants,

use rounded scissors, continue plane beyond edge of
trephination
H. Stripping Descemet from donor; under BSS, under
microscope, use Trypan blue
I. Sew safely, align epithelial edges, avoid needle perforation
III. Manage Complications
A. No bubble? Try again in another place.
B. Still no bubble? Manual dissection: soften eye,
rounded blade without fixation of globe, hydro or
visco dissection tricks
C. Microperforation: Can usually continue
D. Double chamber POD 1: May have microperforation from dissection or suture; try air injection
E. Macroperforation: Convert to PKP
Cornea
47
Deep Anterior Lamellar Keratoplasty: Why You

Should Be Performing It With a Femtosecond Laser
Marjan Farid MD
I. Deep Anterior Lamellar Keratoplasty (DALK)
A. Definition
B. Replace entire corneal stroma while retaining the
patients Descemet membrane and endothelium
C. Disease targeted lamellar surgery
D. Anwar big bubble technique
1. Baring of Descemet membrane from stroma
2. Discard all of the stroma
3. Full-thickness donor minus endothelium
sutured on
II. Femtosecond Laser Technology
A. Photodisruption
B. Creates precise cuts at specified depths
C. Infinite custom trephination possibilities
D. Procedure
1. First step: Standard nonpenetrating femtosecond
laser zigzag incision (leave about 70 microns post
bridge uncut)
2. Second step: Baring of Descemet membrane
using big bubble technique: Femtosecond laser
can create a track for blunt tip cannula insertion;
decreases risk of perforation with a needle.
3. Third step: Remove entire stroma and discard.
4. Fourth step
a. Wipe off donor endothelium and suture on
the donor graft.
b. If Descemet membrane was perforated, proceed with full-thickness transplant.
V. Visante OCT
1. Mushroom
A. Excellent apposition of native Descemet membrane

to donor
2. Top-hat
B. Results
3. Zigzag
4. Christmas tree
III. Femtosecond Laser Zigzag Incision
A. Angled smooth anterior edge
B. Better donor-host transition
C. Hermetic wound seal
IV. Zigzag DALK
A. Combined big-bubble DALK technique with femtosecond laser zigzag incision
B. Indications
1. Keratoconus (KC)
2. Corneal ectasia
3. Stromal scarring or dystrophies
C. Benefits
1. No risk of endothelial rejection. Especially good
in the young KC patient (stromal rejection still
possible).
2. Rapid wound healing with custom trephination
3. Extraocular surgery
4. Easily converted to full-thickness penetrating
keratoplasty in case of Descemet perforation
1. Retrospective comparison of keratoconus eyes

status post zigzag corneal transplantation: DALK
(14 eyes) vs. PKP (46 eyes)
2. No statistically significant difference in:
a. Best spectacle-corrected visual acuity
(BSCVA): logMAR 0.15 vs. 0.19 at 6 months
b. Topographical astigmatism: 3.07 D vs. 3.87
D at 6 months
c. Manifest astigmatism: 2.5 D vs. 3.01 D at 6
months
VI. Conclusion
A. Femtosecond laser zigzag incision guides needle
insertion into posterior stroma, allowing baring of
Descemet membrane.
B. In cases of Descemet rupture, convert to a fullthickness transplant, retaining the benefits of the
zigzag trephination.
C. Zigzag DALK results in excellent recovery of
BSCVA and astigmatism, comparable to fullthickness zigzag transplants.
48
References
1. Farid M, Steinert RF. Deep anterior lamellar keratoplasty performed with the femtosecond laser zigzag incision for the treatment
of stromal corneal pathology and ectatic disease. J Cataract Refract
Surg. 2009; 35(5):809-813.
2. Price FW Jr, Price MO, Grandin JC, Kwon R. Deep anterior lamellar keratoplasty with femtosecond-laser zigzag incisions. J Cataract
Refract Surg. 2009; 35(5):804-808; erratum in: J Cataract Refract
Surg. 2009; 35(7):1325.
3. Chan CC, Ritenour RJ, Kumar NL, Sansanayudh W, Rootman DS.
Femtosecond laser-assisted mushroom configuration deep anterior
lamellar keratoplasty. Cornea 2010; 29(3):290-295.
4. Buzzonetti L, Laborante A, Petrocelli G. Refractive outcome of
keratoconus treated by combined femtosecond laser and bigbubble deep anterior lamellar keratoplasty. J Refract Surg. 2011;
27(3):189-194.
5. Mosca L, Fasciani R, Mosca L, et al. Graft rejection after femtosecond laser-assisted deep anterior lamellar keratoplasty: report of 3
cases. Cornea. Epub ahead of print 3 Jun 2011.
Cornea
Cornea
Section IV: Corneal Transplantation Penetrating and Pediatric Keratoplasty
49
PK: When I Choose PK Instead of Descemet-Stripping

Patient Selection in Keratoplasty: When Is Penetrating Keratoplasty Preferred

to Lamellar Keratoplasty?
Kenneth Mark Goins MD
Purpose
To review those clinical situations where, for the average corneal surgeon who performs penetrating keratoplasty (PK), deep
anterior lamellar keratoplasty (DALK), and Descemet-stripping
endothelial keratoplasty (DSEK), the patient may be better
served by PK.
Introduction: A Paradigm Shift

In the 21st century, there is a paradigm shift from penetrating to
lamellar keratoplasty (LK). DALK, which preserves the recipient
endothelium and eliminates immune-mediated endothelial rejection, has been introduced as an alternative to PK in eyes with
keratoconus and stromal opacities attributable to dystrophies,
degenerations, trauma, and microbial keratitis. Conversely,
endothelial keratoplasty offers the advantage of preservation of
normal corneal stroma and provides rapid visual rehabilitation,
thereby replacing PK as the surgical treatment of choice in most
cases of endothelial dysfunction.
It is generally accepted that the benefits of LK of all types
include a decreased risk for allograft rejection, reduced astigmatism, improved wound integrity and less susceptibility to blunt
trauma, decreased incidence from intraoperative suprachoroidal
hemorrhage, and better maintenance of the anterior chamber
angle, with reduced glaucoma development. In essence, LK
exchanges only the pathologically defective tissue layers, reduces
the chance for adverse events, and provides faster visual recovery. With the ascension of LK, PK is being used less often. Nevertheless, there are certain indications for which PK will remain.
The purpose of this paper is to evaluate those situations in which
LK may be a less desirable option.
How does PK fare as a keratoplasty procedure? In 2011, the
goal of keratoplasty surgery of all types is six-fold, as stated by
Terry et al.7
1. A consistent and smooth surface topography with little to
no change in preoperative astigmatism
2. Predictable and stable corneal power after transplantation
3. Tectonically stable globe that is safe from injury or infection
4. Successful transfer and maintenance of corneal endothelium
5. An optically pure cornea devoid of interface opacity
6. Last but not least, a procedure that is easily and quickly
adopted into clinical practice (ie, easily performed by surgeons of various backgrounds and experiences)
Despite the advances in suture techniques, tissue adhesives,
and wound construction (ie, femtosecond laser), PK does not
consistently achieve the first 3 goals of keratoplasty surgery.
However, PK does fulfill the last 3 goals of keratoplasty surgery
(ie, 4, 5, and 6). It is very important that the corneal surgeon be
able to recognize those situations where the clinical benefits of

PK still outweigh the negative attributes (ie, 1, 2, and 3).
It should be noted that PK is not fairly judged in comparison
to its LK counterparts. For example, the reported average visual
results after PK are quite varied, and in the scientific literature
they are often influenced by nonexcluded comorbidities, such as
glaucoma, AMD, cystoid macular edema, and other factors. PK
has a major advantage over LK surgery of all types, by providing
an optically pure corneal window that is devoid of an interface
that could be susceptible to haze, scarring, wrinkles, and infectious organisms (ie, as reported with DALK and DSAEK).
Surgeon Factors in the Selection Process

Surgeon training and experience are perhaps the most important
factors in the selection process, for if a procedure is so difficult
that it can only be performed by a few surgeons, that particular
procedure is less likely to become mainstream. The Eye Bank
Association of America (EBAA) 2010 donor statistical data
suggest that this may be true for DALK in the United States (ie,
there has been a slow increase in procedures over time), whereas
the opposite is true for endothelial keratoplasty (EK), which has
become widely accepted.
Similar to PK in the 20th century, the technology and techniques of EK have advanced dramatically over the past 10 years,
making the procedure easier to perform with a secondary benefit
of transfer of surgical skills to resident and fellowship training
programs. The same cannot be said for DALK; however, it is
anticipated that a similar transformation will occur in the future.
It can also be said that the excellent outcomes seen with PK for
keratoconus and anterior corneal scars may be responsible for
the slow transition to DALK in the United States.
Patient Factors in the Selection Process

Monocular vs. binocular vision status
In general, the patient with monocular vision status should have
the best procedure that allows a rapid return to average daily living activities. If concomitant procedures such as triamcinoloneassisted vitrectomy, IOL exchange, iris reconstruction, and/or
seton placement are necessary, the corneal surgeon may want to
consider a full-thickness graft to have better visualization so as
to reduce the chance for intraoperative complications. Similarly,
the monocular patient with severe bullous keratopathy and anterior corneal scarring may have faster vision recovery with a PK
instead of EK.
Age and longevity
In the elderly patient who suffers from systemic complications
(ie, COPD, coronary artery disease, malignancy, etc.), restoration of vision with one surgery may be more beneficial than that
seen with multiple-stage procedures. In this situation, the full-
50
thickness surgery is more likely to be completed, without further

enhancement procedures (ie, re-bubble or repositioning of the
DSAEK button, excimer laser phototherapeutic keratectomy,
etc.), at the expense of slower visual return. Surgeon experience,
of course, is an interrelated function in this decision-making
process.
Specific Situations to Consider

Long-term corneal edema
In patients with endothelial dysfunction who have long-standing
disease that is associated with collagen disruption and subepithelial scar formation, PK may offer a more rapid and better
final visual acuity because it provides an optically pure cornea. It
may take months to years before anterior corneal haze resolves
over time after DSAEK, which may hinder patient functioning,
depending upon individual need. In the monocular patient, who
needs rapid visual recovery, the full-thickness graft may actually
be preferred.
Anterior segment reconstruction
The patient with endothelial dysfunction (namely, pseudophakic
bullous keratopathy) with an anterior chamber (AC) IOL and
vitreous incarceration into the anterior segment may actually
be better served by PK, IOL exchange, and anterior vitrectomy.
This procedure can be done in one setting as apposed to a staged
vitrectomy and IOL exchange, followed by DSAEK, which is
commonly done by many corneal surgeons today. There are,
however, short-term outcome studies that suggest that retention of fixed AC IOLs in the setting of EK can be successful and
appropriate. At the current time, findings within our practice
at Iowa suggest that 5-year EK graft survival in the setting of
AC IOL retention may be less than desirable. Regardless of the
procedure performed, these patients are at high risk for cystoid
macular edema, glaucoma, and allograft rejection. The Boston
keratoprosthesis, an alternative type of PK, should be considered
if multiple allograft rejections have occurred in this particular
setting.
Previous failed keratoplasty
In the setting of a failed PK, the surgeon has the option of repeat
PK or EK. EK ensures a very rapid recovery of vision in most
cases; however, if the patient is contact lens intolerant with
disabling astigmatism that is not amenable to laser vision correction, a PK would be preferred.
Previous or active keratitis
The decision to perform DALK over PK may be difficult to
discern in the setting of ocular infection, for inflammation and
Cornea
edema may preclude accurate endothelial cell assessment. Persistent epithelial defect (PED) may prevent adequate assessment of
the posterior cornea due to corneal haze and swelling. Anterior
segment imaging with confocal microscopy is important in the
decision process to rule out atypical pathogens and to determine
endothelial cell morphology. As a rule of thumb, if the patient
is young, the cornea stroma is compact, and there is no history
of hydrops, herpes simplex, or varicella zoster endotheliitis, it
would be most appropriate to proceed with DALK. The benefits of DALK include a better posterior corneal curvature with
reduced wavefront aberrations, less peripheral anterior synechiae
formation and glaucoma, the potential for longer graft survival,
and the ability to use older donor tissue. If there is a question as
to whether the disease process has affected the endothelium, a
traditional PK should be considered.
Conclusion
The purpose of this presentation is to determine when is it appropriate to use PK in the setting of LK of all types. With proper preoperative evaluation using anterior segment imaging techniques
and patient/physician discussion, the proper treatment modality
may be determined in these difficult cases. PK is a procedure that
can be performed very well by most corneal specialists, and it
still has a great role in the management of our patients.
References
1. Anshu A, Parthasarathy A, Mehta JS, Htoon HM, Tan DTH.
Outcomes of therapeutic deep lamellar keratoplasty and penetrating keratoplasty for advanced infectious keratitis. Ophthalmology
2009; 116:615-623.
2. Tan DTH, Anshi A, Mehta JS. Paradigm shifts in corneal transplantation. Ann Acad Med Singapore. 2009; 38:332-339.
3. Sutphin JE, Goins KM, Wagoner MD. Deep anterior lamellar keratoplasty: when should it replace penetrating keratoplasty? Am J
Ophthalmol. 2009; 148:629-631.
4. Goins KM. Surgical alternatives to penetrating keratoplasty II:
endothelial keratoplasty. Int Ophthalmol. 2008; 28:233-246.
5. Pramanik S, Musch DC, Sutphin JE, Farjo AA. Extended long-term
outcomes of penetrating keratoplasty for keratoconus. Ophthalmology 2006; 113:1633-1638.
6. Tan DTH, Anshu A. Anterior lamellar keratoplasty: back to the
futurea review. Clin Exp Ophthalmol. 2010; 38:118-127.
7. Terry MA. Endothelial keratoplasty: clinical outcomes in the two
years following deep lamellar endothelial keratoplasty (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc.
2007; 105:530-563.
Cornea
51
Failed PK: How I Choose Between Repeat PK and

Descemet-Stripping Endothelial Keratoplasty
Alan N Carlson MD
I. Background
Roles of the ideal cornea guide surgical principles and
decision making:
A. Structural goals: Maintaining or restoring structural
integrity as part of the wall of the eye
B. Optical transmission: Maintaining or restoring optical clarity for transmission of light
C. Refractive contribution: Contributing to the focusing power of the optical system
D. Cosmetic: Maintaining or restoring normal corneal
physiology to help preserve the appearance of a normal eye
II. Reasons for PK Failure
A. Immunologic: Rejection
B. Surface disease: Multifactorial
C. Infection
D. Trauma
E. Neurotrophism
F. Glaucoma
G. Ectasia
H. Poor wound healing
III. Connect the Dots
How did the patient get from point A (PK) to point B
(failed PK)?
IV. Advantages of Proceeding With DSAEK to Treat a
Failed PK
A. Structural integrity
Relying on previous graft-host junction healing
rather than repeating a process that requires suture
supported healing for 12-24 months
B. Surface disease
A complex multifactorial insult on the corneal surface related to neurotrophism, medication toxicity,
lid margin disease, evaporative dry eye, etc.all factors that are typically worse with patients undergoing full repeat PK in comparison to DSAEK.
C. Recovery
Typically much faster with DSAEK than with PK,
allowing for a faster taper of medications, including steroids. Also, recovery is more predictable
with DSAEK than with PK in terms of astigmatism,
refractive stability, and a reasonably predictable
small hyperopic shift; PK is much more prone
toward high degrees of astigmatism and refractive

instability.
D. Intraoperative considerations
DSAEK may be more technically challenging in
some cases that have, for example, synechiae or
anterior chamber IOLs; however, there is the
advantage of having a closed system should you
encounter hemorrhage or vitreous prolapse.
E. Infection
The long-term risk of infection is much less with
DSAEK, as suture exposure and breakage contributes to this late in post-PK patients. There is a growing sense that the closed system offered by DSAEK,
along with the transplantation of less tissue, may
result in a lower risk of serious early infections than
is seen with PK.
V. When is DSAEK after failed PK a bad idea?
A. Return to basic principles: When IA, IB, IC, ID are
compromised or not restored with surgery.
B. Structural integrity issues, such as a severely compromised graft-host junction (GHJ), tissue over-ride,
or severe ectasia peripheral to the previous graft.
These cases are often better handled with a repeat
PK with special attention to wound maintenance
than with DSAEK, which would not repair the
problem. There are some cases where a GHJ wound
revision would help restore structural integrity and
surface contour and can be combined with DSAEK.
C. Optical transmission may be compromised by a scar
from previous infection or ulceration, and if this is
visually significant, it needs to be factored into consideration favoring PK rather than DSAEK surgery.
D. Refractive considerations may lead to repeat PK if
tissue distribution mismatch or previous healing
resulted in large amounts of irregular astigmatism.
Unless the patient was a successful rigid contact lens
wearer, repeat PK would be the better choice from
an optical standpoint.
E. Cosmetic considerations are usually a lower priority, but in general DSAEK offers the advantage
of having less swelling, redness, and ptosis after
surgery. However, there are also those cases where
stromal scarring from infection, inflammation, or
chronic edema is better treated with repeat PK than
with DSAEK.
VI. Special Cases and Other Considerations
A. Traumatic aphakia and aniridia can make DSAEK
problematic, as poor donor attachment can lead to
posterior dislocation of the donor tissue.
52

B. Hypotony, particularly if severe, requires special
attention to make DSAEK a viable option when
repeating a graft. Some of these cases are better
managed with PK.
C. Retinal considerations: Combination surgical procedures that include extensive vitreoretinal surgery
often require a temporary keratoprosthesis for better visibility and are therefore better treated with PK
than with DSAEK.
D. Failed PK in combination with an anterior chamber
IOL and shallow chamber are typically poor candidates for DSAEK unless the chamber is deepened,
and the IOL may need to be exchanged for a posterior IOL, sutured if there is no capsular support.
E. End-stage glaucoma patients may be considered at
unacceptable risk from the elevated IOP created to
attach the donor tissue with DSAEK.
F. Patients with previous glaucoma filtering surgery
including tube shunts require attention relative to
their proximity to DSAEK donor tissue and also air
bubble evacuation and the risk for potential hypotony, and therefore some of these patients are better
treated with PK.
VII. Clinical Examples
A. Patient DD
Failed PK O.S. resulting from severe trauma. Traumatic aniridia and aphakia along with vitreous
prolapse into anterior chamber and poor visibility.
High-risk patient better suited for repeat PK than
for DSEK. Tissue dislocation would be difficult to
manage.
B. Patient MV
Neisseria meningitidis endophthalmitis requiring
extensive vitrectomy, so decision for PK was made
to allow for intraoperative temporary keratoprosthesis for better visibility for extensive PPV.
Cornea
VIII. Summary
Eyes with a failed PK are usually complex, resulting from a variety of issues. It is important whenever
possible to understand the reasons behind the donor
tissue failure. There is great incentive to take advantage of the newer DSAEK techniques that offer more
rapid healing; better structural integrity, refractive
stability, and predictability; reduced medications; and
decreased infection risk long term. Unfortunately, not
every patient with a failed PK can be reduced to purely
endothelial dysfunction. Additional considerations may
require PK to re-establish both optical and structural
considerations.
References
1. Jun B, Kuo AN, Afshari NA, Carlson AN, Kim T. Refractive
change after Descemet stripping automated endothelial keratoplasty
surgery and its correlation with graft thickness and diameter. Cornea 2009; 28(1):19-23.
2. Kharod BV, Carlson AN. Corneal transplantation using the Descemets stripping endothelial keratoplasty technique. Expert Rev
Pharmacoecon Outcomes Res. 2007; 7(2):137-142.
3. Caldwell MC, Perfect JR, Carlson AN, Proia AD. Candida glabrata
endophthalmitis following penetrating keratoplasty. J Cataract
Refract Surg. 2009; 35(3):598-602.
4. Patel M, Challa P, Afshari NA. Descemets stripping automated
endothelial keratoplasty in a patient with four glaucoma tubes. Ann
Ophthalmol (Skokie). 2010; 42 Spec No: 20-23.
5. Duarte MC, Herndon LW, Gupta PK, Afshari NA. DSEK in eyes
with double glaucoma tubes. Ophthalmology 2008; 115(8):1435.
e1.
6. Clements, JL, Bouchard CS, Lee WB, et al. Retrospective review of
graft dislocation rate associated with Descemet stripping automated
endothelial keratoplasty after primary failed penetrating keratoplasty. Cornea 2011; 30(4):414-418.
7. Hwang RY, Gauthier DJ, Wallace D, Afshari NA. Refractive
changes after Descemet stripping endothelial keratoplasty: a simplified mathematical model. Invest Ophthalmol Vis Sci. 2011;
52:1043-1054.
Cornea
53
Failed PK: How I Choose Between Repeat PK and

a Keratoprosthesis
I. Outcomes and Complications of Boston
Keratoprosthesis (KPro, Type 1)
A. Outcomes
1. Retention rate of 80%-100% (range of
follow-up: 8.5-33.6 months)
2. Visual acuity
a. 1-year: 23%-43% with vision greater than or
equal to 20/40 or 20/50, and 59%-77% of
patients with greater than or equal to 20/10020/200
b. 5-year: 29%-100% with vision greater than
or equal to 20/200 at 5 years (n = 10 patients)
B. Complications
1. Retroprosthetic membrane
2. Corneal melt
3. Progression of glaucoma
4. Endophthalmitis
C. References
1. Zerbe BL, Belin MW, Ciolino JB; Boston Type
1 Keratoprosthesis Study Group. Results from
the multicenter Boston Type 1 Keratoprosthesis
Study. Ophthalmology 2006; 113:1779-1784.
2. Chew HF, Ayres BD, Hammersmith KM, et
al. Boston keratoprosthesis outcomes and
complications. Cornea 2009; 28:989-996.
3. Aldave AJ, Kamal KM, Vo RC, Yu F. The
Boston type I keratoprosthesis: improving
outcomes and expanding indications.
4. Greiner MA, Li JY, Mannis MJ. Longerterm complications with the Boston type I
keratoprosthesis at the University of California,
Davis. Ophthalmology. Epub ahead of print 12
Mar 2011.
II. Outcomes for Repeat Penetrating Keratoplasty (PK)
A. Graft survival
Six years of Wills Eye Institute cornea records were
recently reviewed to identify all patients who had
undergone 3 or more PKs. Of 45 patients identified,
third grafts had an 89% 1-year survival; 78%,
2-year survival; and 53%, survival at last follow-up
(median 4.3 years). The median survival time for the
third graft was 12.8 years for Fuchs dystrophy, 5.2
years for herpetic keratitis, 4.0 years in keratoconus,
3 years for pseudophakic bullous keratopathy, 2.3
years for iridocorneal endothelial syndrome, and
2 years in stromal dystrophies. Previous glaucoma
procedures and corneal neovascularization were

statistically significant risk factors for failure of a
third graft.
B. Visual acuity
Forty percent of patients with a third graft had a
visual acuity of 20/100 or better at postoperative
year 1, 33% at postoperative year 2 and 3, and 20%
had better than 20/100 at last follow (mean: 4.3
years).
C. Reference
1. Yildiz EH, Hoskins E, Fram N, et al. Third or
greater penetrating keratoplasties: indications,
survival and visual outcomes. Cornea 2010;
29:254-259.
III. Questions That Help Guide Decision Between Repeat
PK and KPro
A. Who is the patient?
1. Age
Boston KPro affords more rapid visual recovery
in amblyogenic age, but it takes a long time
to develop complications (RPM, glaucoma,
endophthalmitis).
a. Nallasamy S, Colby K. Keratoprosthesis:
procedure of choice for corneal opacities in
children? Semin Ophthalmol. 2010; 25:2428.
b. Aquavella JV, Gearinger MD, Akpek EK, et
al. Pediatric keratoprosthesis. Ophthalmology
2007; 114:989-994.
2. Status of fellow eye
3. Compliance
B. Why did the graft(s) fail? Are these factors
modifiable in the future?
1. Limbal stem cell deficiency. Not modifiable
without limbal stem cell transplant. Favor KPro.
a. Chemical injury
b. Aniridia
c. Autoimmune disorders (TENS, MMP) still
suffer high complication rates from KPro.
A titanium KPro backplate and adjunctive
immunomodulation may enhance outcomes.
2. Recurrent herpetic keratitis
a. Did patient receive postoperative prophylactic
oral antivirals?
Prophylactic oral acyclovir has been shown
to decrease herpes-related recurrences and
54

episodes of rejection and improve graft
survival. (Garcia DD, Farjo Q, Musch DC,
et al. Effect of prophylactic oral acyclovir
after penetrating keratoplasty. Cornea 2007;
26:930-934. van Rooij J, Rijneveld WJ,
Remeijer L, et al. Effect of oral acyclovir
after penetrating keratoplasty for herpetic
keratitis). If patient did not receive oral
prophylaxis, favor repeat PK with antiviral
therapy.
b. Very promising results of improved vision
and a low complication rate in 14 patients
with history of failed graft and herpetic disease who underwent Boston KPro. (Khan BF,
Harissi-Dagher M, Pavan-Langston D, et al.
The Boston keratoprosthesis in herpetic keratitis. Arch Ophthalmol. 2007; 125:745-749.)
If received adequate oral prophylaxis, favor
KPro.
3. Neurotrophic complications
a. Depends on level of neurotrophia. (Pavan
Langston D, Dohlman CH. Boston
keratoprosthesis treatment of herpes zoster
neurotrophic keratitis. Arch Ophthalmol.
2008; 115:S21-S23.)
b. If had PK without tarsorrphaphy, favor
repeat PK and tarsorrhaphy. If had PK
with temporary tarsorrhaphy, still with
neurotrophic complications, favor KPro.
Cornea
4. Endothelial failure
a. Following rejection: If not treated with
adequate steroids or if poor compliance with
steroid therapy in past, favor repeat PK. If
treated with aggressive steroids in past, favor
KPro.
b. Following subsequent surgery (cataract,
glaucoma): If current status of the eye is now
pseudophakic and/or with better controlled
IOP, favor repeat PK.
c. Late endothelial failure: If patient had many
years of clear graft but now with late failure,
favor repeat PK.
Additional Selected Readings

1. Colby KA, Koo EB. Expanding indications for the Boston keratoprosthesis. Curr Opin Ophthalmol. 2011; 22(4):267-273.
2. Traish AS, Chodosh J. Expanding application of the Boston type
1 keratoprosthesis due to advances in design and improved postoperative therapeutic strategies. Semin Ophthalmol. 2010; 25:239243.
3. Ament JD, Todani A, Pineda R, et al. Global corneal blindness
and the Boston keratoprosthesis type I. Am J Ophthalmol. 2010;
149:537-539.
4. Ament JD, Stryjewski TP, Ciolino JB, et al. Cost-effectiveness of the
Boston keratoprosthesis. Am J Ophthalmol. 2010; 149:221-228.
Cornea
55
Transplantation of Congenitally Opaque Corneas:

Pearls and Pitfalls
Stuart I Brown MD
The experiences of pediatric keratoplasty (PKP) in 72 infants
eyes with congenitally opaque corneas (COC) performed
between 23 and 10 years ago were reviewed and evaluated
toward determining factors important in achieving transparent
grafts for at least 10 years. All surgeries were performed before 4
months of age.
Classification
Congenitally opaque corneas were classified as follows:
r 1FUFSTBOPNBMZPSDFOUSBMDPSOFBMPQBDJUJFTXJUIPSXJUIout PAS: Nineteen of the 22 corneal grafts remained transparent more than 10 years. Glaucoma occurred in 2 eyes
of the 3 failures.
r 1BSUJBMTDMFSPDPSOFB 14$
PSDFOUSBMDPSOFBMPQBDJUJFT
extending to part but not all of the limbus: Eight of 15
grafts remained transparent more than 10 years. Glaucoma only occurred in 5 of the 7 failures.
r 4DMFSPDPSOFB 4$
UPUBMMZPQBRVFDPSOFBT5ISFFPG
grafts remained transparent more than 10 years. Glaucoma occurred in 3 of the 4 failures.
r $POHFOJUBMHMBVDPNB5XPPGFZFTSFNBJOFEUSBOTQBSFOU
more than 10 years.
r 'PSDFQTSVQUVSFPG%FTDFNFUNFNCSBOF0OFFZF
remained transparent more than 10 years.
Exclusions
r 5XFMWFFZFTXJUIBNJYUVSFPGDMBTTJGJDBUJPOTIBEUSBOTQBSent grafts but were lost to follow-up between 8 months
and 8 years after surgery.
r 5IJSUFFOFZFTXFSFFYDMVEFECFDBVTFPGFYUSFNFBMUFSBtions requiring multiple procedures: corneal keloid (4
eyes), corneal ectasia (3 eyes), microphthalmos < 15 millimeters (3 eyes), and buphthalmos (3 eyes).
Key Factors Toward Success

r .PTUTVDDFTTFTIBEBSFMBUJWFMZOPSNBMBOBUPNZ JF QSFTence of lens and majority of iris).
r *OUBDUEPOPSFQJUIFMJVN XIJDIOFFETQSPUFDUJPOEVSJOH
surgery in eyes with PSC or SC
r (MBVDPNB FTQFDJBMMZUIFUSFBUNFOU XBTBTTPDJBUFEXJUI
two-thirds of failures.
r 0QFSBUJWFJEFOUJGJDBUJPOBOEMPDBUJPOPGQVQJM JSJTEFGFDUT
and chamber dimensions by transillumination facilitates
sizing of graft, locating initial incision, and maintaining
integrity of lens capsule.
r -BSHFEPOPST PGBUMFBTU
SFMBUJWFUPFYDJTFEIPTU
This requires accurate deep placement of sutures, especially when dealing with irregularities in host corneal
thickness.
r 4VUVSFSFNPWBMCFUXFFOBOEXFFLTQPTUPQFSBUJWFMZJO
vascularized and between 3 and 6 weeks in nonvascularized corneas
r 'SFRVFOUUPQJDBMDPSUJDPTUFSPJETGPSBUMFBTUNPOUIT
r "NCMZPQJBUIFSBQZGPSTFDPOEFZFJTDSJUJDBM CVUDPNQMJance is difficult.
r 5SBOTQMBOUBUJPOPGVOJMBUFSBMDPOHFOJUBMDPSOFBMPQBDJGJDBtion provides excellent vision if carried out in the first 3
months.
r $PSUJDPTUFSPJEJOEVDFEQSFTTVSFFMFWBUJPOTPDDVSJOJOGBOUT
as well as adults.
The above was important toward our achieving long-term
success: 85% in Peters, 66% in PSC, and 40% in SC.
56
Cornea
Pediatric Keratoprosthesis: Are We There Yet?

Introduction
Neonatal cornea opacity may be acquired from forceps injury,
birth canal infection, or trauma, but it is most frequently congenital as a result of Peters anomaly, glaucoma, nondescript dysgenesis, or more rarely congenital hereditary endothelial dystrophy.
Traditional management involves patching with dilatation to
enable light to enter the eye beyond the confines of the cornea
scarring, optical iridectomy in more severe cases, and cornea
transplantation. These are not just small eyes with cloudy corneas; they are subject to a variety of ophthalmic pathology as a
result of associated glaucoma, inflammation, and vitreoretinal
disease. The treating ophthalmologist is aware of the potential
for amblyopia, and parental concerns increase the pressure for
early diagnosis and therapy.
Controversies
In monocular cases some feel that no therapy is warranted since
a reasonably normal development is possible with one eye. There
is considerable disagreement in the literature as to the results of
penetrating keratoplasty. Published reports often differ in the criteria for success or failure: graft clarity, graft survival, and visual
acuity, as well as the length of follow-up. In any event, we are
aware of the significantly elevated incidence of allograft rejection
in infants compared with adults.
Keratoprosthesis
Following the reintroduction of the modified Boston type I
device, our team has advocated keratoprosthesis as a primary
procedure and most definitely when a standard cornea transplant
has failed. While a cornea transplant is often performed by a
single cornea surgeon, we feel strongly that the combination of
comorbidity and propensity for inflammation in these infants
demands a team approach. Thirty percent of our cases are associated with some form of vitreoretinal disease, glaucoma is not
infrequent, and the prospects of amblyopia are ever present.
Logistical Considerations
A multispecialty team consists of cornea, pediatrics, glaucoma,
and retina subspecialties. Medical records must be reviewed, and
a dedicated postoperative management system developed in conjunction with the referring ophthalmologist, who likely resides in
a distant location. Prior authorization and insurance issues cannot be avoided. At the very least, exams under anesthesia as well
as the actual surgery will involve both cornea and retina services,
so coordination and scheduling will be important.
Procedural Options
Removal of the clear or opaque natural lens is performed in all
cases. Elevated pressure can be addressed prior to, during, or following the placement of a keratoprosthesis. We feel strongly that
all cases should have the benefit of a pars plana vitrectomy with
360 degree direct inspection of the peripheral retina. An aphakic

powered device is always implanted. In the presence of ocular
surface irregularities, an amniotic membrane may be considered
in addition. All cases receive a hydrophilic bandage lens and are
placed on a prophylactic antibiotic regimen with appropriate
doses of steroids to control inflammation.
Advantages
Advantages include a rapid progression to best potential acuity,
absence of discomfort, ease of amblyopia treatment, and excellent optics without astigmatism or anisometropia. Direct and
facile observation of the posterior pole is possible from the first
day, and of course graft rejection will not occur.
Disadvantages
Disadvantages include the operative team approach with multispecialty follow-up, long-term antibiotic prophylaxis, maintaining a bandage lens, and the fact that retroprosthetic membranes
occur in 30% of cases.
Anticipated Improvements
As with all forms of therapy, improvements will occur over time.
Management of the ocular surface, new methods for measuring
IOP, and perhaps systemic measures to combat the ever-present
potential for inflammation will be welcome.
Conclusions
For some groups such as ours infant keratoprosthesis is the best
option to afford the development of useful vision. The inherent
difficulties in dealing with multifactorial pathology as well as the
related logistical complexities must not be allowed to cloud the
value of the surgical procedure. Others will be more comfortable
in awaiting a broader dissemination prior to adopting the technology.
Video Summary
The cornea opacification is varied and compounded by previous failed keratoplasty. Dysgenesis combined with conjunctiva
overgrowth make recognition of the central cornea difficult. A
Flieringa ring precedes a nonpenetrating outline deepened with
a diamond blade. Hemostasis is important. Severing adherent
synechiae and iris dysgenesis can have a variety of presentations.
Shunts may be preexisting. Lensectomy and anterior vitrectomy
precede placement of the assembled KPro, followed by the bandage lens. Pars plana vitrectomy is the final step in all cases.
Cornea
Selected Readings
1. Dana MR, Schaumberg DA, Moyes AL, Gomes JA. Corneal transplantation in children with Peters anomaly and mesenchymal dysgenesis. Ophthalmology 1997; 104(10):1580-1586.
2. Rao KV, Fernandes M, Gangopadhyay N, Vemuganti GK, Krishnaiah S, Sangwan VS. Outcome of penetrating keratoplasty for
Peters anomaly. Cornea 2008; 27(7):749-753.
3. Yang LL, Lambert SR, Drews-Botsch C, Stulting RD. Long-term
visual outcome of penetrating keratoplasty in infants and children
with Peters anomaly. J AAPOS. 2009; 13(2):175-180.
4. Aquavella JV, Gearinger MD, Akpek EK, McCormick GJ. Pediatric
keratoprosthesis. Ophthalmology 2007; 114(5):989-994.
5. Aquavella JV. Keratoprosthesis in the treatment of congenital corneal opacity. Contemp Ophthalmol. 2008; 7(8):1-6.
57
58
Section V: Ocular Surface Disease Therapeutics
Cornea
What to Do for Corneal Neovascularization

I. Background
Corneal neovascularization (NV) is the common
denominator of a vast number of corneal and ocular
surface pathologies. As such, it is associated with the
second most frequent cause of blindness worldwide,
cornea scarring. Not only is the invasion of the normally avascular and transparent cornea by blood vessels a consequence of many pathologies, but it can also
cause or amplify corneal pathologies by promoting
leaky vessels that lead to lipid deposition and amplified immune responses (eg, as seen in the setting of
corneal transplantation). For all these reasons, a better
understanding of the pathophysiologic mechanisms of
corneal NV and effective therapeutic measures is an
integral part of corneal and external disease management.
II. Pathogenic Mechanisms of Corneal NV
A. Molecular and cellular bases of corneal avascularity
1. Soluble vascular endothelial growth factor
(VEGF) receptors
2. Ectopic expression of epithelial VEGF receptor
(VEGF sink)
3. Pigment epithelium-derived factor (PEDF)
4. Other antiangiogenic factors
B. Molecular and cellular bases of corneal NV
1. Vascular endothelial cell proliferation and migration
2. Pterygium
E. Limbal stem cell insufficiency states
F. Autoimmune disorders: PUK
G. Meibomian gland dysfunction
H. Neurotrophic disorders
I. Corneal transplant
J. Contact lensrelated (hypoxia)
IV. Therapeutic Approaches
A. Optimize treatment of underlying etiology or
offending agent
1. Infection
2. Contact lens
B. Surgical
1. Excision of lesion (pterygium)
2. Superficial keratectomy amniotic membrane
grafting
3. Limbal stem cell grafting
C. Laser
D. Photodynamic therapy
E. Diathermy/cautery
F. Pharmacologic
1. Conventional drugs
Efficacy: Corticosteroids > NSAIDs >
cyclosporin A
2. Stromal matrix degradation and role of matrix

metalloproteinases (MMPs)
3. Proangiogenic factors
2. Biologic or small molecule approaches
a. Inflammatory cytokines
a. Directed at one or more pathogenic factors
b. VEGFs
b. Anti-VEGFs
i. bevacizumab (Avastin)
c. Platelet-derived growth factor
ii. ranibizumab (Lucentis)
d. Fibroblast growth factor
iii. others
III. Principal Clinical Etiologies of Corneal NV
c. Others
A. Infections
1. Herpetic
2. Bacterial
3. Chlamydial
B. Chemical burns: Alkali > acid
C. Penetrating trauma
D. Degenerations
1. Terriens
References
1. Clements JL, Dana R. Inflammatory corneal neovascularization:
etiopathogenesis. Semin Ophthalmol. 2011. In press.
2. Cursiefen C, Chen L, Saint-Geniez M, Hamrah P, Jin Y, Rashid S,
Pytowski B, Persaud K, Wu Y, Streilein JW, Dana R. Nonvascular
VEGFR-3 expression by corneal epithelium maintains avascularity
and vision. Proc Nat Acad Sci USA. 2006; 103:11405-11410.
Cornea
3. Gupta D, Illingworth C. Treatments for corneal neovascularization: a review. Cornea. Epub ahead of print 11 Mar 2011. PMID:
21403519.
4. Dastjerdi M, Saban DR, Okanobo A, Nallasamy N, Sadrai Z,
Chauhan SK, Hajrasouliha A, Dana R. Effects of topical and subconjunctival bevacizumab (Avastin) in high-risk corneal transplant
survival. Invest Ophthalmol Vis Sci. 2010; 51:2411-2417.
5. Dastjerdi MH, Al-Arfaj KM, Nallasamy N, Hamrah P, Jurkunas
U, Pineda R, Pavan-Langston D, Dana R. Topical bevacizumab in
the treatment of corneal neovascularization: results of a prospective open-label, non-comparative study. Arch Ophthalmol. 2009;
127:381-389.
59
60
Cornea
Amniotic Membrane Grafts:

Uses and Controversial Uses
Roy S Chuck MD PhD
Pterygium Surgery With Amniotic Membrane
An ideal pterygium surgery should achieve three principal goals:
low recurrence rate, lack of complications, and satisfactory cosmetic appearance. A number of methods for surgical excision
and prevention of recurrence have been reported, with widely
variable results. Although conjunctival autografts have shown
success and are considered the gold standard, they are oftentimes
not able to cover large defects created in double-head primary
or large recurrent pterygia. Furthermore, concerns have been
raised for those in whom there exist free conjunctival shortages
or who may require future glaucoma-filtering surgeries. In addition, because of graft suturing, this method has the disadvantage
of a relatively longer surgery time when compared with the bare
sclera technique. Also, it carries the risk of complications such as
granuloma formation and giant papillary conjunctivitis, as well
as significant patient discomfort after surgery. In recent years, a
better understanding of the role of limbal stem cells and widespread use of amniotic membrane in pterygium surgery have led
to the development of new surgical techniques, especially involving fibrin glue, for this disease. Some of these techniques will be
presented and reviewed in this talk.
Although not without its limitations, amniotic membrane
transplantation has proven successful in reducing recurrence
rates in both primary and recurrent pterygia, with minimal complications and good cosmetic results. This is accomplished by
thoroughly removing the abnormal pterygium tissue, by restoring the matrix in the excision area through the use of the amniotic membrane, which provides a new basement membrane for
rapid re-epithelialization and a stromal matrix for suppressing
scarring, and by decreasing inflammation with postoperative use
of topical corticosteroids. The main advantage of using amniotic
membrane resides in its ability to restore large excised areas (eg,
in double-head or large recurrent pterygia), where a conjunctival autograft is not possible. It is also advantageous in cases in
which the conjunctiva is already scarred from previous surgery
or has to be reserved for a possible glaucoma-filtering surgery.
However, further randomized, controlled studies are required to
scientifically evaluate the efficacy of the membrane in general, as
well as different membrane preparations. Perhaps the generation
of a synthetic membrane, in which collagen or polymers are
used as matrices to incorporate growth factors, cytokines, antimicrobial peptides, and other substances tailored toward specific
clinical applications, will be possible in the future. This could
pave the way to a standardized product with known quantities
of desired ingredients with hopefully even more predictable outcomes.
Controversies and Limitations of Amniotic

Membrane
The various inhibitory and proinflammatory cytokines and other
molecules identified in amniotic membrane may have contradictory actions. For example, IL-6 and IL-8 are proinflammatory,
and, conversely, IL-10 and IL-1ra are anti-inflammatory, yet
both are present in amniotic membrane. Similarly, the presence
of various growth factors such as epithelial growth factor (EGF)
can support epithelial growth and transforming growth factor
(TGF) wound healing. However, under some circumstances TGF
can also promote scar tissue formation and counter the antiadhesive or scar suppressing action proposed for the membrane
in preventing corneal and conjunctival cicatrization.
A likely mechanism by which amniotic membrane delivers its
beneficial effect is as a substrate or basement membrane transplant for new epithelial cells to migrate on, expand, and adhere
to. Use of membrane as a bandage to cover inflamed or exposed
areas, due to injury or surgery, not only favorably influences the
healing process but also has a dramatic favorable effect on the
symptoms of pain or discomfort.
Many differences can also exist between amniotic membranes
obtained from different donors. Even for the same donor, it is
general practice to obtain numerous pieces of amnion for use in
multiple operations. Therefore, some pieces could be from locations closer to the placenta and others distant to it. The thickness of these locations can vary, as can the morphology of the
amniotic epithelium. Age, race, parity, gravidity, and duration
of gestation may all contribute to variability of specimens. It is
important to keep in mind that membranes used in transplantation are far from standardized across donors and even within the
same donor.
Finally, several differences may exist between different membranes depending on whether they are used fresh or preserved
and, in the case of the latter, depending on the mode and duration of preservation. Most methods employed in the preservation
of the membrane affect it in some manner. The weight of the
evidence available supports the notion that the viability of the
tissue components of amniotic membrane is not essential for its
biological effectiveness. Until the effect of different methods of
preservation and storage has been fully evaluated and standardized, success or failure of the membrane should be qualified by
the method of preservation employed.
Cornea
61
Scleral Contact Lenses: Resolving Ocular

Surface Issues?
IV. Indications for Scleral Contact Lenses
I. Definition of Scleral Contact Lenses

Scleral contact lenses are large-diameter rigid gas-permeable lenses ranging from 15 to 24 mm in diameter
(vs. hybrid lens or large silicone lens).
II. Lens Types
III. History of Scleral Contact Lenses: Old Concept, but
New Tool
A. 1500s: Leonardo da Vinci first described contact
lenses
B. 1880s: Glass contact lenses first produced
1. FE Muller: Blown glass scleral lenses for his own
severe myopia (1887)
2. AE Fick: Filling the glass lens shells with a thick
grape sugar solution to promote movement of
the lens on the cornea (1888).
3. E Kalt: Glass contact shell for keratoconus (1888)
C. 1920s: First preformed ground glass scleral shell fitting sets
D. 1930s: Polymethylmethacrylate (PMMA) with
impression molding
E. 1950s: Smaller PMMA corneal lens vs. larger scleral
lens
F. 1960s: More flexible and oxygen permeable soft
hydrogel materials
G. 1980s: Breathable rigid gas permeable (RGP)
materials
H. 1990s: Silicone hydrogels and newer, high-oxygen
permeable polymers with new design concepts to
manufacture scleral lenses
I. Today
1. Pullum scleral lens (Kenneth Pullum) extensively
used overseas
2. Boston scleral lens (aka Prosthetic Replacement
of the Ocular Surface Ecosystem [PROSE], Perry
Rosenthal) primarily in the United States
A. Corneal irregularity
1. Primary corneal ectasias: Keratoconus, keratoglobus, pellucid marginal degeneration, Terrien
marginal degeneration
2. Secondary/postsurgical corneal ectasias: PostLASIK and post-PRK, irregular corneas due to
trauma or corneal graft
B. Protection of ocular surface
1. Severe ocular surface disease: Sjgren syndrome,
Stevens-Johnson syndrome, mucous membrane
pemphigoid, graft vs. host disease, persistent
epithelial corneal defects, neurotrophic ulcers,
corneal anesthesia (herpes simples virus, herpes
zoster ophthalmicus, trigeminal ablation)
2. Limbal stem cell deficiency: Aniridia, radiation,
chemical burns
3. Lagophthalmos: Facial palsies, ectropion, exophthalmos, eyelid coloboma
C. Cosmesis: Corneal opacities, ptosis
V. Pros and Cons of Scleral Contact Lenses
A. Advantages
1. Larger size (up to 25 mm , ~ the size of a quarter)
for excellent protection of the ocular surface
2. Vaulting the cornea without limbal bearing
3. Masking surface irregularity and independent of
the corneal contour
4. May preserve large tear reservoir
5. More physiological and comfortable with less
decentration
B. Disadvantages
1. Poor surface wetting with reduced oxygen permeability to cornea
2. Challenging and time-consuming to fit
3. Relatively prohibitive costs
4. Difficulty of lens insertion and removal
Table 1. Types of Scleral Contact Lenses

Lens Type
Alternative Name
Corneal
Diameter
Bearing
Tear Reservoir
Up to 12.5 mm
On cornea
None
Corneoscleral
Semi-scleral; Limbal
12.5 to 15 mm
On limbosclera
Limited
Mini-scleral
(Mini) Haptic
15 to 18 mm
On sclera
Slightly limited
(Full) Scleral
Haptic
18 to 24 mm
On sclera
Ample
62

VI. Designs and Costs of Scleral Contact Lenses
A. Designs
1. Traditional: Serial conics (optical, transition, and
landing zones) with fenestration
2. Newer: Custom-lathe, spline functions, fluid ventilation
B. Costs
1. Custom fit and manufactured for specific pathology and patient needs
2. Considerable chair and fitting time
3. Approximately $4000 per lens (PROSE; $5000
one eye and $7600 both eyes, EyeWorld, 2011)
4. Lens maintenance and replacement costs
Cornea
VII. Special Applications of Scleral Contact Lenses

A. As therapeutic reservoirs
1. Autologous serum
2. Growth factors (EGF, NGF)
3. Bevacizumab (Avastin)
B. As surgical adjuncts
1. Post-LASIK keratoneuralgia
2. Corneal collagen crosslinking
3. Ocular surface reconstruction or limbal stem cell
transplantation
Cornea
63
Dry Eye: A Burning Issue Revisited

Definition of Dry Eye Disease

Chronic pain syndrome associated with fluctuating vision.
Selected Readings
1. Asbell PA, Lemp M, eds. Current Treatment and Diagnosis in Dry
Eye Disease. New York: Thieme Medical Publishers; 2006.
DEWS (Dry Eye WorkShop): www.tearfilm.org/dewsreport/
2. Introduction to the Report of the 2007 International Dry Eye
WorkShop (DEWS). Ocul Surf. 2007; 5(2):69-70.
3. The definition and classification of dry eye disease: report of the
Definition and Classification Subcommittee of the International
Dry Eye WorkShop (2007). Ocul Surf. 2007; 5(2):75-92.
4. The epidemiology of dry eye disease: report of the Epidemiology
Subcommittee of the International Dry Eye WorkShop (2007).
Ocul Surf. 2007; 5(2):93-107.
5. Methodologies to diagnose and monitor dry eye disease: report of
the Diagnostic Methodology Subcommittee of the International Dry
Eye WorkShop (2007). Ocul Surf. 2007; 5(2):108-152.
MGD Report: (Meibomian Gland Dysfunction Workshop)

9. Nichols KK. The International Workshop on Meibomian Gland
Dysfunction: introduction. Inv Ophthalmol Vis Sci. 2011; 52:19171921.
10. Nichols KK, Foulks GN, Bron AJ, et al. The International Workshop on Meibomian Gland Dysfunction: executive summary. Inv
Ophthalmol Vis Sci. 2011; 52:1922-1929.
11. Nelson JD, Shimazaki J, Benitez-del-Castillo JM, et al. The International Workshop on Meibomian Gland Dysfunction: report of the
Definition and Classification Subcommittee. Inv Ophthalmol Vis
Sci. 2011; 52:1930-1937.
12. Knop E, Knop N, Millar T, Obata H, Foulks GN. The International
Workshop on Meibomian Gland Dysfunction: report of the Subcommittee on Anatomy, Physiology, and Pathophysiology of the
Meibomian Gland. Inv Ophthalmol Vis Sci. 2011; 52:1938-1978.
13. Green-Church KB, Butovich I, Willcox M, et al. The International
Workshop on Meibomian Gland Dysfunction: report of the Subcommittee on Tear Film Lipids and Lipid-Protein Interactions in
Health and Disease. Inv Ophthalmol Vis Sci. 2011; 52:1979-1993.
6. Design and conduct of clinical trials: report of the Clinical Trials

Subcommittee of the International Dry Eye WorkShop (2007).
Ocul Surf. 2007; 5(2):153-162.
14. Schaumberg DA, Nichols JJ, Papas EB, Tong L, Uchino M, Nichols
KK. The International Workshop on Meibomian Gland Dysfunction: report of the Subcommittee on the Epidemiology of, and
Associated Risk Factors for, MGD. Inv Ophthalmol Vis Sci. 2011;
52:1994-2005.
7. Management and therapy of dry eye disease: report of the Management and Therapy Subcommittee of the International Dry Eye
WorkShop (2007). Ocul Surf. 2007; 5(2):163-178.
15. Tomlinson A, Bron AJ, Korb DR, et al. The International Workshop on Meibomian Gland Dysfunction: report of the Diagnosis
Subcommittee. Inv Ophthalmol Vis Sci. 2011; 52:2006-2049.
8. Research in dry eye: report of the Research Subcommittee of

the International Dry Eye WorkShop (2007). Ocul Surf. 2007;
5(2):179-193.
16. Geerling G, Tauber J, Baudouin C, et al. The International Workshop on Meibomian Gland Dysfunction: report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction. Inv Ophthalmol Vis Sci. 2011; 52:2050-2064.
17. Asbell PA, Stapleton FJ, Wickstrm K, et al. The International
Workshop on Meibomian Gland Dysfunction: report of the Clinical Trials Subcommittee. Inv Ophthalmol Vis Sci. 2011; 52:20652085.
64
Surgery by Surgeons
| Cornea
2011 Surgery by Surgeons Update

Stephanie J Marioneaux MD
With this years passage of legislation in Kentucky that allows

optometrists to perform laser surgery, the American Academy
of Ophthalmologys partnership with ophthalmic subspecialty
and state societies on the Surgery by Surgeons campaign becomes
even more important in protecting quality patient eye care across
the country.
In 2009-2010, the Eye M.D.s serving on the Academys Secretariat for State Affairs collaborated with the leadership of many
state ophthalmology societies on legislative battles in which
optometry continued to push for expanded scope of practice.
Leadership of subspecialty societies provided essential support
in some of these battles. Success was reached with surgery provisions removed and/or bills defeated in Idaho, Maine, Mississippi, Nebraska, South Carolina, Texas, Washington and West
Virginia.
In 2011, the stakes were raised with the disappointing outcome in Kentucky. The Kentucky legislation also includes the
creation of an independent optometric board; no other board or
state agency has the authority to question what constitutes the
practice of optometry. The Secretariat for State Affairs continues
to work diligently with state society leaders in South Carolina,
Nebraska, Tennessee and Texas to ensure that a Kentucky outcome is not repeated. For example, following the passage of legislation in Kentucky, fundraising material by organized optometry in Tennessee made it clear that they would like to replicate
optometrys outcome in Kentucky and have begun discussions
with state legislators.
The Surgical Scope Fund (SSF) is a critical tool of the Surgery
by Surgeons campaign to protect patient quality of care. The
Academy relies not only on the financial contributions via the
SSF by individual Eye M.D.s but also on the contributions made
by ophthalmic state, subspecialty and specialized interest societies. The Cornea Society contributed to the SSF in 2010, and the
Academy counts on its contribution in 2011.
The results in Kentucky should be viewed as a failure neither
of the SSF nor of the Academys Secretariat for State Affairs,
which geared up immediately to strategize with Kentucky
Academy physician leadership. In a period of 15 days, with no
advanced warning, optometry was able to introduce and pass a
bill in the Kentucky state legislature and secure its passage into
law. A SSF disbursement actually assisted with critical media
buys and powerful public messaging favoring ophthalmology
and quality patient eye care for the citizens of Kentucky. This
should be a lesson to each Eye M.D. in the country about the
importance of contributions to your state eyePAC and to the
SSF.
Leaders of The Cornea Society are part of the American
Academy of Ophthalmologys Ophthalmology Advocacy Leadership Group (OALG), which has met for the past four years in
the Washington DC area to provide critical input and to discuss

and collaborate on the American Academys advocacy agenda.
The Cornea Society remains a crucial partner to the Academy
in its ongoing federal and state advocacy initiatives. As a 2011
Congressional Advocacy Day (CAD) partner, The Cornea Society ensured a strong presence of cornea specialists to support
ophthalmologys priorities as over 350 Eye M.D.s had scheduled
CAD visits to members of Congress in conjunction with the
Academys 2011 Mid-Year Forum in Washington DC.
At the state level, the Academys Surgery by Surgeons campaign has demonstrated a proven track record. Kentucky was an
outlier; the Academys SSF has helped 31 state ophthalmology
societies reject optometric surgery language.
Help us help you protect our patients and quality eye care.
The Academys Surgical Scope Fund remains a critical tool in the
Surgery by Surgeons campaign. The Academys Surgical Scope
Fund Committee works hard on your behalf to ensure the ongoing strength and viability of the SSF.
Thomas Graul MD (Nebraska): Chair
Arezio Amirikia MD (Michigan)
Kenneth P Cheng MD (Pennsylvania)
Bryan S Lee MD PhD (Maryland): Consultant
Richard G Shugarman MD (Florida)
Stephanie J Marioneaux MD (Virginia)
Bryan S Sires MD PhD (Washington)
Andrew Tharp MD (Indiana)
Ex-officio members:
Cynthia A Bradford MD
Daniel J Briceland MD
The SSF is our collective fund to ensure that optometry does not
legislate the right to perform surgery. Do not forget about Congress, where ophthalmologys influence is through OPHTHPAC.
Just as a strong state presence is needed, so do we need to remain
strong in the federal arena. While OPHTHPAC is the third largest medical PAC, a mere 15% of the Academys membership
contribute.
The Kentucky legislation is not in the best interests of patient
safety and quality patient care. Ophthalmology needs the active
support of every memberand this includes contributions to the
Surgical Scope Fund, state eye PACs and OPHTHPAC.
Please respond to your SSF Committee and OPHTHPAC
Committee colleagues when they call on you and your subspecialty society to contribute. There are some decisions that require
thought, but donating $500 to the SSF and OPHTHPAC is the
easy answer for you and your patients. Do it today. Do it now.
Section VI: Cornea Potpourri
Cornea
65
Straighten Up and Listen: Ergonomics for Your

Aching Back
Anna Kitzmann MD
Its been a long day; youve seen 40 patients and performed many
laser vision correction procedures. You leave work, and driving home you note stiffness in your lower back and neck. You
turn on your heated seat despite the 90 degree outside temperature and soon feel relief from your back and neck discomfort.
However, a disturbing thought runs through your mind: is the
stiffness related to all the awkward positioning and static muscle
contractions throughout the day? Will this stiffness and/or pain
become chronic? You are not alone, as many of your colleagues
also have had musculoskeletal symptoms and pain.
The prevalence of musculoskeletal disorders (MSDs) has been
reported over the past decade in the ophthalmic literature and at
various meetings. While the survey instruments and populations
studied are variable, an approximate prevalence of neck pain is
33%-69%; lower back pain, 38%-80%; and both neck and back
pain, 52%-54%.1 In a recent survey conducted by the Academy
in 2009 during its biennial random survey of its members, 951
members responded, with 30% experiencing current neck problems and 20% experiencing current upper or lower back, hand,
or arm problems related to working.2
However, none of these surveys had a control group of nonophthalmologists to determine if the prevalence of MSD symptoms in ophthalmologists is higher. At the University of Iowa
and Mayo Clinic, we used a standard survey instrument to determine MSD symptoms in eye care physicians and family medicine
physicians. In this study, eye care physicians had a statistically
significantly higher prevalence of neck, hand/wrist, and low back
pain compared to family medicine physicians.3
In response to published reports and data from the recent
Academy membership survey, the Academy Board of Trustees
has commissioned a task force composed of 6 ophthalmologists,
a group of ergonomics specialists, and Academy leadership. Our
goals are (1) to inform academy members about common occupational musculoskeletal disorders and how to prevent them
and (2) to develop ergonomic guidelines/standards for ophthalmic equipment and encourage their adoption by the device
industry.
While the task force works with ergonomics specialists, what
can we do now to help members? We can educate members
about ergonomic postures in the office and operating room and
share advice on preventative exercises.
Recommendations for Decreasing Risks for MSDs4

In the operating room
r "EKVTUTFBU UBCMF BOETDPQFUPBDDPNNPEBUFBOFVUSBM
posture.
r 6TFTFBUTXJUIQBEEFEMVNCBSTVQQPSUBOEBEKVTUBCMF
height features to maintain a neutral pelvis.
r ,FFQUIFMVNCBSTQJOFJODPOUBDUXJUIUIFCBDLTVQQPSU
r 3FTUFMCPXTBUTJEFTBOEXSJTUTPOBQBEEFETVQQPSU
r %POPUFMFWBUFBCEVDUUIFBSNT
At the slitlamp and laser
r "EKVTUFRVJQNFOUBOEQBUJFOUQPTJUJPOUPNBJOUBJOOFVUSBM
posture.
r 6TFTFBUTXJUIIFJHIUBOEBOUFSJPSUJMUGFBUVSFTUPBDDPNmodate sitting postures.
r 5JMUUIFQFMWJTBOUFSJPSMZUPNBJOUBJOUIFMVNCBSMPSEPTJT
r 3FTUFMCPXTPOMZPOBGPBNQBEEFEPSWJTDPFMBTUJDTVSGBDF
Will any of this advice translate to reduced MSDs in ophthalmologists? In the Netherlands, 50% of dentists adopted all
or most and an additional 40% adopted some of their dental
professions ergonomic recommendations, with a resulting 72%
reduction or disappearance of their main MSD complaint.5
Perhaps we should follow the advice of baseball player Dante
Bichette Jr: Keep your head up and dont let anything get to
you. Always keep good posture.
Optimal positioning during examinations and in the operating room will be shown with photographic representation of
incorrect and improved positioning. A noon-time symposium on
Ergonomics in Ophthalmology will be presented on Monday,
October 24.
References
1. Dhimitri KC, McGwin G Jr, McNeal SF, et al. Symptoms of musculoskeletal disorders in ophthalmologists. Am J Ophthalmol. 2005;
139:179-181.
2. AAO Biennial Survey of Members. 2009. Unpublished.
3. Kitzmann AS, Fethke NB, Baratz KH, et al. A survey study of musculoskeletal disorders among eye care physicians compared to family medicine physicians. Ophthalmology. In press.
4. Mark JL, Wertz FD, Dhimitri KC. Work-related musculoskeletal
disorders in ophthalmologists. Tech Ophthalmol. 2005; 3:54-61.
5. Droeze EF, Jonsson H. Evaluation of ergonomic interventions to
reduce musculoskeletal disorders of dentists in the Netherlands.
Work 2005; 25:211-220.
66
Cornea
Corneal Imaging: Confocal, OCT, and Ultrasound

BiomicroscopyWhat Are They Good For?
Majid Moshirfar MD, Brent Betts BS
I. Evolution of Corneal Imaging
A. Corneal imaging has grown from traditional keratometry to advanced imaging modalities capable of
3-dimensional analysis of the cornea.
B. These new imaging modalities have uses in refractive surgery, the diagnosis of corneal pathology, and
accurate assessment of anterior chamber measurements.
II. Cornea Imaging Today: In vivo confocal microscopy
(IVCM)1
A. How does it work?
1. Light focuses on tissue through an objective lens
and is reflected back to through objective lens
and into a detection apparatus.
2. Takes information from tissue without the need
for physical sectioning
B. Types of IVCM
1. Tandem scanning-based confocal microscopy
(TSCM)
a. Simple design, but low intensity of illumination
b. Inefficient illumination causes it to appear
bright to the patient and causes patient discomfort.
2. Slit-scanning confocal microscopy (SSCM)
a. Slit aperture allows increased light throughput, which improves field brightness and contrast vs. TSCM
b. Lower illumination is more comfortable for
patients.
3. Laser scanning confocal microscopy (LSCM)
a. Provides faster scanning of the tissue plane via
laser technology
b. High-depth resolution and high contrast
allow for more detailed view of tissue vs.
SSCM and TSCM
C. Clinical applications
1. LASIK
a. Corneal sub-basal nerve layer assessment
i. Patel et al fellow eye study comparing
sub-basal nerve density with SSCM in femtosecond laser and microkeratome created
flaps2
ii. Nerve density was significantly decreased
(P < .001) following surgery with both
methods of flap creation, but returned to

normal levels 36 months following surgery.
iii. Femtosecond flap creation was not associated with faster corneal reinnervation.
b. Corneal haze assessment
i. McLaren et al assessed corneal haze in 35
post-LASIK eyes and 36 untreated eyes via
SSCM.3
ii. Image intensity was 30% lower in the
stroma of LASIK treated eyes (P < .001).
Brightness was not significantly different
between the groups
c. Flap healing
i. Petroll et al assessed corneal keratocyte
response following flap creation with the
IntraLase FS60 Laser.4
ii. Keratocyte activation was found in 10 of
30 eyes, but interface haze was trace. The
authors recommended a higher steroid
dose to decrease keratocyte activation.
2. Cell density measurements
a. Analysis in LASIK/PRK
i. Amoozadeh et al examined stroma and
endothelial cell counts following LASIK
and PRK.5
ii. Anterior stromal keratocyte count significantly decreased 6 months following
LASIK/PRK.
iii. Stromal and endothelial cell counts were
not significantly different after surgery
between the groups.
b. Analysis in Fuchs dystrophy
i. Hecker et al examined anterior keratocyte
populations in corneas that required PKP
for Fuchs dystrophy.6
ii. Anterior keratocytes decreased 54%-63%
in Fuchs dystrophy.
iii. The authors felt anterior stromal changes
may contribute to degrading vision following an endothelial keratoplasty.
3. Infectious keratitis
a. Acanthamoeba: Shirashi et al used LSCM to
monitor tissue response to treatment against
Acanthamoeba and adjust the treatment regimen as needed.7
Cornea
b. Fungal keratitis: Takezawa et al found LSCM

to be an effective tool in quick diagnosis of
fungal keratitis and monitoring the effect of
therapy in FK.8
c. Vaddavalli et al found SSCM had 88.3%
sensitivity and 91.1% specificity in identifying
fungal filaments and Acanthamoeba cysts.9
d. Curzat et al has recently shown increased corneal epithelial dendritic cell density correlates
with decreased sub-basal nerve density in
infectious keratitis.10
e. Acanthamoeba, fungal, and bacterial keratitis
all cause temporary neurotrophic keratopathy.
f. Loss of nerve plexus more severe in Acanthamoeba keratitis.
III. Cornea Imaging Today: Ultrasound Biomicroscopy
(USBM)
A. Cost effective real-time imaging
B. Clinical applications
1. Corneal layer imaging: Corneal thickness
Reinstein et al showed USBM generates highly
repeatable corneal layer readings and suggest this
may have application in keratoconus screening
and assessing candidacy for LASIK.11
2. Keratoconus: Javadi et al used USBM to confirm
acute hydrops following DALK in a patient with
keratoconus.12
3. Phakic IOL implantation: Choi et al found using
USBM to measure sulcus-to-sulcus horizontal
diameter for an implantable contact lens to be
more accurate in creating an ideal ICL vault than
traditional white-to-white horizontal corneal
diameter.13
IV. Cornea Imaging Today: Optical Coherence Tomography (OCT)14
A. How does it work?
Measurement is based on the delay of light reflected
from the tissue back to the detection apparatus.
B. Types of OCT
1. Time domain (TD-OCT)
a. Tissue depth is detected serially, but image
acquisition is slower than newer technologies
due to mechanical parts.
b. Penetrates deeper through sclera and iris due
to longer wavelength
2. Fourier domain (FD-OCT) or spectral domain
OCT (SD-OCT)
a. Tissue depth detected as a spectrum
b. Higher definition and faster than TD-OCT
67
C. Clinical applications
1. LASIK
a. Postoperative analysis of LASIK flaps created
with femtosecond laser can be accurately
assessed with FD-OCT.15
b. SD-OCT provides more consistent flap thickness estimates than TD-OCT 1 month following LASIK.16
2. Anterior segment pathology detection
SD-OCT has recently been shown to be useful in
the detection of Salzmann nodular degeneration,
corneal dystrophy of Bowman layer type II, and
granular dystrophy, among others.17
3. Wound healing assessment
AS-OCT has recently been shown to help assess
quality of epithelial wound healing in patients
who are wearing therapeutic contact lenses.18
4. Anterior chamber (AC) dimensions
Doors et al analyzed AC dimensions with
TD-OCT before and after implantation of irisfixated phakic IOLs (pIOL). The authors found
most measurements did not differ significantly
from preop to postop, with a range of agreement
between preop and postop measurements to be
between 0.24 mm and 0.29 mm. There was a
significant difference between preop and postop
distance from the nasal edge of the pIOL to the
endothelium and the distance from the pIOL to
the crystalline lens.19
III. Future Directions
A. Confocal microscopy: Multiphoton fluorescence
and second harmonic generation microscopy
1. Tan et al used this technology ex vivo to monitor
corneal structural changes in infectious keratitis.
2. Furthermore, this imaging modality may increase
the ability to diagnose the cause of infectious
keratitis.20
B. Ultrasound biomicroscopy: Acoustic radiation force
imaging
1. May have application in measuring the elastic
qualities of the cornea
2. Hollman et al used radiation force imaging to
measure lens elasticity in vivo.21
C. Optical coherence tomography
1. Applications in determining IOL power calculations in patients who have had laser vision correction
2. Tang et al found OCT was statistically similar to
established formulas in determining IOL power
for cataract surgery and have an ongoing study
looking at OCTs application in IOL power
determination following laser refractive surgery.22
68
Cornea
References
1. Guthoff RF, Zhivov A, Stachs O. In vivoconfocal microscopy, an
inner vision of the corneaa major review. Clin Experiment Ophthalmol. 2009; 37(1):100-117.
13. Choi KH, Chung SE, Chung TY, Chung ES. Ultrasound biomicroscopy for determining Visian implantable contact lens length in
phakic IOL implantation. J Refract Surg. 2007; 23(4):362-367.
2. Patel SV, McLaren JW, Kittleson KM, Bourne WM. Subbasal nerve
density and corneal sensitivity after laser in situ keratomileusis: femtosecond laser vs mechanical microkeratome. Arch Ophthalmol.
2010; 128(11):1413-1419.
14. Konstantopoulos A, Yadegarfar G, Fievez M, Anderson DF,

Hossain P. In vivo quantification of bacterial keratitis with optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;
52(2):1093-1097.
3. McLaren JW, Bourne WM, Patel SV. Standardization of corneal

haze measurement in confocal microscopy. Invest Ophthalmol Vis
Sci. 2010; 51(11):5610-5616.
15. Rosas Salaroli CH, Li Y, Zhang X, et al. Repeatability of laser in

situ keratomileusis flap thickness measurement by Fourier-domain
optical coherence tomography. J Cataract Refract Surg. 2011;
37(4):649-654.
4. Petroll WM, Bowman RW, Cavanagh DH, Verity SM, Mootha V,

McCulley JP. Assessment of keratocyte activation following LASIK
with flap creation using the IntraLase FS60 Laser. J Refract Surg.
2008; 24(8):847.
5. Amoozadeh J, Aliakbari S, Behesht-Nejad AH, et al. Confocal
microscopy of corneal stroma and endothelium after LASIK and
PRK. J Refract Surg. 2009; 25(suppl):S963-S967.
6. Hecker LA, McLaren JW, Bachman LA, Patel SV. Anterior keratocyte depletion in Fuchs endothelial dystrophy. Arch Ophthalmol.
2011; 129(5):555-561.
7. Shiraishi A, Uno T, Oka N, et al. In vivo and in vitro laser confocal microscopy to diagnose acanthamoeba keratitis. Cornea 2010;
29(8):861-865.
8. Takezawa Y, Shiraishi A, Noda E, et al. Effectiveness of in vivo
confocal microscopy in detecting filamentous fungi during clinical
course of fungal keratitis. Cornea 2010; 29(12):1346-1352.
9. Vaddavalli PK, Garg P, Sharma S, et al. Role of confocal microscopy in the diagnosis of fungal and Acanthamoeba keratitis. Ophthalmology 2011; 118(1):29-35.
10. Cruzat A, Witkin D, Baniasadi N, et al. Inflammation and the nervous system: the connection in the cornea in patients with infectious
keratitis. Invest Ophthalmol Vis Sci. 2011; 52(8):5136-5143.
11. Reinstein DZ, Archer TJ, Gobbe M, Silverman RH, Coleman DJ.
Repeatability of layered corneal pachymetry with the Artemis very
high-frequency digital ultrasound arc-scanner. J Refract Surg. 2009;
26(9):646-659.
12. Javadi MA, Feizi S, Kanavi MR, et al. Acute hydrops after deep
anterior lamellar keratoplasty in a patient with keratoconus. Cornea 2011; 30(5):591-594.
16. Hall RC, Mohamed FK, Htoon HM, Tan DT, Mehta JS. Laser in
situ keratomileusis flap measurements: comparison between observers and between spectral-domain and time-domain anterior segment optical coherence tomography. J Cataract Refract Surg. 2011;
37(3):544-551.
17. Vajzovic LM, Karp CL, Haft P, et al. Ultra high-resolution anterior
segment optical coherence tomography in the evaluation of anterior corneal dystrophies and degenerations. Ophthalmology 2011;
118(7):1291-1296.
18. Pang CE, Vanathi M, Tan DTH, Mehta JS. Evaluation of corneal
epithelial healing under contact lens with spectral-domain anterior
segment optical coherence tomography (SD-OCT). Open Ophthalmol J. 2011;5:51.
19. Doors M, Berendschot TT, Hendrikse F, Webers CA, Nuijts RM.
Value of preoperative phakic intraocular lens simulation using
optical coherence tomography. J Cataract Refract Surg. 2009;
35(3):438-443.
20. Tan HY, Sun Y, Lo W, et al. Multiphoton fluorescence and second
harmonic generation microscopy for imaging infectious keratitis. J
Biomed Opt. 2007; 12(2):024013.
21. Hollman KW, ODonnell M, Erpelding TN. Mapping elasticity in
human lenses using bubble-based acoustic radiation force. Exp Eye
Res. 2007; 85(6):890-893.
22. Tang M, Li Y, Huang D. An intraocular lens power calculation
formula based on optical coherence tomography: a pilot study. J
Refract Surg. 2010; 26(6):430.
Cornea
69
Corneal Topography and Tomography Interpretation

for the Cataract Surgeon: Implications for Premium
and Toric IOLs
Randy J Epstein MD
I. Cataract surgeons should, at this point, perform preop
topography on every patient
A. Even if you dont use any premium IOLs
B. Cataract surgery is refractive surgery!
II. The Role of Topography and Tomography
A. Preoperative
1. Defining preop astigmatism
2. Assessment of ocular surface disease
a. Dry eyes
b. Epithelial basement membrane dystrophy
(EBMD)
3. Detecting occult keratoconus
4. Staging of the cataract
B. Intraoperative
1. Placement of incision (preferably in steep axis)
2. Placement of the IOL
C. Postoperative
1. Dealing with the unhappy patient
2. Planning for enhancements
III. Upgrades for Premium IOLs
Should include postop enhancements: limbal relaxing
incisions (LRIs), PRK, LASIK. If you dont do corneal
refractive surgery/IOL XC, establish a relationship with
a refractive surgeon who does.
IV. Refractive Lens Exchange (RLE)
A. My preferred procedure for patients > 60 years old
who are interested in refractive surgery
B. Azar study: LASIK is OK for older (presbyopic)
patients.
C. RLE with a multifocal IOL addresses both distance
and near issues most effectively.
1. Treats lens (cataract)-induced higher-order
aberrations and lenticular astigmatism
2. Avoids dissatisfaction with quality of vision
3. Eliminates post-LASIK IOL calculation hassle
for inevitable cataract surgery
V. Objective Exclusion Criteria for Presbyopia-Correcting
IOLs
A. Astigmats (>1.5D of corneal astigmatism)
B. Macular pathology (epiretinal membranes, drusen):

We frequently check macular OCT preop
C. Abnormal corneas
1. Keratoconus, prior cornea and/or refractive surgery
2. Severe ocular surface disease (EBMD, keratoconjunctivitis sicca)
D. Glasses-wearing low myopes
VI. Presbyopia-Correcting IOLs: Complications
A. IOL power errors
B. Miscommunication with patients (mono-vision, etc.)
C. Surgical complications
1. Backup IOLs need to be available: 3-piece multifocals with PMMA haptics
2. No backup for toric IOL, so prepare for LRIs
(another reason for topography)
VII. Presbyopia-Correcting IOLs: Postop Issues
A. Younger patients may have issues with contrast sensitivity, etc. when used for RLE.
B. Failure to underpromise/overdeliver
C. Use -2.50D glasses for demo of what near visual
acuity would have been like without multifocal IOL.
D. Use topography to illustrate residual astigmatism
(which is usually the issue).
E. Have a low threshold for offering no charge PRK/
LASIK touch-ups.
F. Dissatisfaction after implantation of multi-focal
IOLs: De Vries, et al. J Cataract Refract Surg. 2011.
1. Ametropia and/or astigmatism was the main
cause of blurred vision.
2. 84% successfully treated: brimonidine, refractive
correction, refractive surgery, YAG.
3. Only 4% required IOL exchange.
VIII. Toric IOLs
A. Astigmatism correction always takes precedence
over presbyopia Rx!
1. I rarely use multifocal IOLs if over +1.5D corneal
cylinder.
2. My comment: You have 3 problems (cataract,
astigmatism, and presbyopia), and we can only
fix 2 at the present time.
70

3. Otherwise patients may wind up with inadequate
uncorrected distance and near vision.
B. Toric/multifocal IOLs
1. Currently investigational but in use in Europe
2. May enable us to treat all 3 problems simultaneously
C. Contraindications to the use of toric IOLs: Not too
many!
A. Pentacam Comprehensive Eye Scanner

1. Most popular example of this technology in the
United States at present (Oculus GmbH, Wetzlar
Germany)
2. Scheimpflug camera: rotates around a meridian
point, captures thin slices of tissue
3. Uses in cataract surgery planning:
a. Holladay Report
b. Nuclear Grading System (PNS) software
2. KC +/- May change with Orange (WaveTec

Vision Systems, Aliso Viejo CA), etc.
D. Toric IOLs with or without LRIs: Preop considerations
1. LRIs: online calculator = ASCRS calculator
(www.ascrs.org)
2. Surgical planning
3. Incision placement: Online toric IOL calculator takes into account your surgically induced
astigmatism (SIA) = (www.acrysoftoriccalculator
.com)
E. Choice of toric IOL is facilitated by careful study of
topography
1. Calculate how much corneal astigmatism you
want to correct when choosing IOL power.
2. Higher powers are now available.
3. Factor in lenticular astigmatism: Ignore it!
4. Use other measurements (like interferometer,
etc.) to corroborate cylinder axis as glasses and
refraction not reliable with cataract
F. Toric IOL positioning
1. Bring topography to the OR.
2. Put axis marks on the eye, using topography as a
guide.
3. Initial partial alignment: Allow for clockwise
rotation.
G. What if there is more astigmatism than a toric IOL
can correct?
1. Not likely with extended power range now available
2. Make incision in steep axis and extend it (Epstein
study)
3. Add LRIs in addition
4. Leave patient with undercorrected astigmatism
5. Augment with later refractive surgery if necessary
Cornea
IX. The Use of Corneal Tomography for Cataract Surgery
1. Fewer ocular issues: OK to use with GLC, AMD,

postops, etc.
3. ? Ocular surface disease (EBMD, dry eyes)
c. Accurate white-to-white measurements

B. Pentacam Holladay Report
1. True corneal power: equivalent K reading
(EKR) at 4.5 mm o.z.
2. Power spread graphs provide a measure of
accuracy (or at least the range).
3. Tangential and pachymetry maps, plus axial
power and standard topography
4. Can demonstrate degree of postrefractive surgery power spread
C. Pentacam Nucleus grading System (PNS) software
1. Can determine density and volume of nucleus
preop
2. Useful for OR phaco parameter presets
3. Objective and reproducible
4. Improves efficiency and safety
5. Documentation
D. IOL exchange techniques: Critical to master with
premium IOLs
References
1. deVries NE, Webers CAB, Wouter RH. Dissatisfaction after
implantation of multifocal intraocular lenses. J Cat Ref Surg. 2011;
37:859-865.
2. Ghanem RC, de la Cruz, J, Tobaigy FM, Ang LPK, Azar DT.
LASIK in the presbyopic age group. Ophthalmology 2007;
114:1303-1310.
3. Wolffsohn JS, Bhogal G, Shah S. Effect of uncorrected astigmatism
on vision. J Cataract Refract Surg. 2011; 37:454-460.
4. Rao S, Konowal A, Murchison AE, Epstein RJ. Enlargement of the
temporal clear corneal incision to treat pre-existing astigmatism.
JRefract Surg. 2002; 18:463-467.
Feel free to contact me at: repstein@chicagocornea.com
Cornea
71
Autologous Serum: Is It Worth the Hassle?

Bennie H Jeng MD
Introduction
Current Indications
Dry eyes
One of the other major indications for the use of autologous
serum is that of dry eyes. Dry eyes can be caused by various etiologies, and the use of autologous serum has been explored in
a number of these. The use of autologous serum has been demonstrated to have success in the treatment of dry eyes associated
with Sjgren syndrome in terms of both clinical response and
patient symptoms. A number of smaller studies have demonstrated the efficacy of autologous serum in patients with dry eyes
secondary to chronic graft vs. host disease. Dry eyes that occur
after various types of keratorefractive surgery have also been
treated with autologous serum, with demonstrated benefits both
in clinical objective findings and in subjective patient symptoms.
Anecdotally, many refractive surgeons will even plan to start
autologous serum at the time of surgery to help maximize healing
response. With a mixed population of different etiologies causing
dry eye syndrome in my own practice, I have found that 90% of
patients achieve symptomatic improvement in their symptoms,
and nearly 100% of patients achieve clinical improvement as
measured by rose bengal staining of the ocular surface.
Since the revival of the use of autologous serum for the treatment of various conditions of the ocular surface approximately
a decade and a half ago, many indications for its use have been
proposed. Some of the most common uses of autologous serum
include the treatment of dry eyes and of persistent epithelial
defects. In addition, autologous serum has also been demonstrated to be effective in the treatment of neurotrophic keratopathy, recurrent erosion syndrome, and superior limbic keratoconjunctivitis.
Neurotrophic keratopathy
Because of the neurotrophic factors that autologous serum is
noted to harbor, including substance P and nerve growth factor,
autologous serum has been used in the treatment of neurotrophic
keratopathy of various etiologies. In one larger study of 14 eyes
of 11 patients, corneal sensitivity as measured by the CochetBonnet esthesiometer improved significantly after treatment with
autologous serum.
The use of autologous serum in ophthalmology has a long history that dates back at least to the 1970s, when autologous
serum was used via a mobile perfusion pump to treat dry eyes.
Subsequently, a report in the rheumatologic literature in 1984
further suggested that autologous serum could be used as a tear
substitute. In the last 15 years or so, the use of autologous serum
has become increasingly popular, and the indications for its
use have expanded rapidly. Many investigators throughout the
world are using autologous serum for the treatment of various
ocular surface disorders. However, despite the reported successes of the use of this product, there are clinical and nonclinical
concerns regarding this therapy that must be addressed. In this
presentation, I will discuss the current indications for the use of
autologous serum for the treatment of ocular surface disorders,
and I will also discuss potential barriers to the use of this therapy, as well as whether or not this therapy is worth the hassle.
Persistent epithelial defects

In 1999, Dr. Kazuo Tsubota and colleagues published an excellent prospective study describing the use of autologous serum in
the treatment of persistent epithelial defects. In this study, 62.5%
of 16 patients with persistent epithelial defects healed with the
use of 20% autologous serum within 1 month. Since the publication of this study, a number of studies have also described the
successful use of autologous serum in the treatment of this condition. Authors have used concentrations of serum ranging from
20% to 100% and have demonstrated a healing rate of defects
between 20% to 60% at 2 weeks, and between 47% to 83%
at 4 weeks. In our own recent study, we found similar results
using 50% autologous serum. In addition, we also found that
the length of time required for healing is directly correlated with
the length of time a persistent epithelial defect has been present.
Thus, consideration should likely be given to earlier treatment
of an epithelial defect with autologous serum in cases that are
at high risk of being nonhealing. Indeed, in line with this idea,
autologous serum has been used in eyes immediately following
surgery (ie, following diabetic vitrectomy surgery in which the
corneal epithelium was debrided and in postpenetrating keratoplasty eyes), demonstrating superior efficacy in healing compared
to controls.
Recurrent erosion syndrome

Recurrent erosions effectively occur because of the lack of ability of the corneal epithelium to heal appropriately in the specific
setting of an irregular basement membrane and/or poor epithelial
adhesion. Thus, it would make sense that autologous serum
could be effective in treating this condition, as it is effective in
treating persistent epithelial defects. Although the serum does not
treat the underlying basement membrane irregularity, basement
membrane polishing in conjunction with the immediate use of
autologous serum eye drops may prove to be beneficial for the
long-term treatment of this debilitating condition.
Indeed the use of autologous serum for the treatment of
recurrent erosion syndrome has been shown to be effective in
reducing the number of recurrences experienced by patients. In
my own practice, I always plan to have patients with recalcitrant
recurrent erosions (after failing an invasive procedure such as
epithelial debridement with basement membrane polishing or
phototherapeutic keratectomy) treated with further basement
membrane polishing followed by immediate use of autologous
serum eye drops. This has proven to be exceptionally effective at
preventing future recurrences.
Superior limbic keratoconjunctivitis
Expanding the use of autologous serum treatment to superior
limbic keratoconjunctivitis has been suggested by some inves-
72
tigators. In one report, 9 of 11 patients responded well to this

therapy, with a decrease in rose bengal and fluorescein staining
as well as an improvement in subjective symptoms.
Potential Barriers to Widespread Use

Potential complications
Although there are very few reports of complications associated
with the use of autologous serum, potential problems such as
deposition of immunoglobulins have been reported. In addition,
the possibility exists for microbial contamination, and indeed,
anecdotal reports of this have been seen. Furthermore, sampleswapping in the laboratory could result in transmission of viral
infections such as hepatitis and HIV from one patient to another.
Laboratory personnel are also at risk for transmission because
they are handling the serum. Thus, it may be advisable that preparation of autologous serum be undertaken only after screening
for transmissible viral infections is done, and that it should be
performed only by trained technicians in controlled laboratory
settings.
Serum preparation
One of the major roadblocks to the widespread use of autologous serum is the limited availability of laboratories authorized
to process whole blood to produce the serum for ocular use. In
the United States, it is particularly difficult to find laboratories
that are willing to perform this processing. This may explain the
relative paucity of published articles coming from the United
States on the topic of autologous serum. Even worldwide, the
protocol for the production of serum also runs into regulatory
and legislative restrictions. Especially in light of the potential
contamination and infection risks associated with production
of the autologous serum, it may be prudent to have regulatory
guidelines in place for the preparation of this product. Perhaps
a standardized protocol for the production of autologous serum
would also aid in overcoming some of these regulatory restrictions.
Lack of an optimized protocol
At this point, there is much evidence in the literature regarding
the success in the treatment of various types of ocular surface
disorders with the use of autologous serum eye drops. However,
most of these studies are retrospective in nature and run the
gamut in terms of the protocol for the production of the serum:
not only do the concentrations of serum in these studies vary
(from 20% to 100%), but the actual processing of the serum varies as well.
The key steps in the production of serum that can result in
differing yields of various growth factors in the product include
the clotting time after drawing blood, as well as the time and
speed of centrifugation of the blood. Variations in these steps
have been demonstrated to yield differing amounts of factors and
vitamins in the blood, and these differing levels can have differing effects on the rate of healing of the ocular surface. The key
components in serum that are likely involved in ocular surface
health and repair include epidermal growth factor, transforming
growth factor, fibroblast growth factor, platelet derived growth
factor, hepatocyte growth factor, nerve growth factor, vitamin
A, vitamin E, fibronectin, and substance P.
Thus, in order to develop regulatory guidelines for the production of autologous serum, the development of a standardized protocol for the manufacture of these drops should also be
Cornea
considered concurrently. In 2005 Liu and colleagues proposed

an optimized protocol for the production of autologous serum
that they showed to be effective at yielding the highest amounts
of these growth factors and vitamins in the serum. While this
protocol has not yet been confirmed by other groups, it could be
a starting block from which government agencies could work to
approve the production of autologous serum more freely.
Patient inconvenience and cost
Patients who need to use autologous serum eye drops often have
to do so for an extended period of time, and thus they will need
to have blood drawn at least every 3 months. Not only is this
inconvenient, but in some cases, patients may not even be medically able to use their own blood for production into autologous
serum. In these cases, allogeneic serum, donated by a family
member, could be considered, but there are ethical considerations with this practice as well. In addition to the inconvenience,
autologous serum can be also expensive; patients in the United
States generally have to pay out-of-pocket for the serum as the
vast majority of insurance carriers do not cover this treatment.
Very recently, however, the Northern California Kaiser Permanente Health Care System (which serves 30% of the population
of northern California) has made autologous serum a covered
benefit, and to date, more than 100 patients have benefited from
this therapy. With any luck, other insurance carriers will also follow suit.
Is it worth the hassle?

In most circumstances, patients who are prescribed autologous serum eye drops have already been treated with all other
standard medical treatment modalities. As such, many of these
patients are facing some sort of an intervention for their next
treatment step: tarsorrhaphy or amniotic membrane graft for
persistent epithelial defects or phototherapeutic keratectomy for
recurrent erosion syndrome, for example. Or, they may be considering prosthetic replacement of the ocular surface ecosystem
(formerly Boston Scleral Lens) for severe dry eyes, which may
require travel to a center that fits these specialty lenses. Thus,
if faced with these alternatives and given the reported efficacy
of autologous serum eye drop therapy, then even in spite of the
inconveniences and the expense to the patient, I believe that
autologous serum eye drops is worth the hassle!
Future Directions
While it would be very interesting to know exactly which factors
are the most efficacious at healing various types of ocular surface
disorders, the greatest challenge that will face ophthalmologists using autologous serum eye drops in the near future is the
ability to attain the production of serum in a standardized yet
efficient, feasible, and cost-effective manner that adheres to local
regulatory guidelines. Well-designed and appropriately powered
prospective clinical trials to test the safety and efficacy of this
therapy (at varying concentrations, with different preparation
methods, and for various indications) would be able to guide
the development of appropriate therapeutic guidelines for use of
autologous serum eyedrops and to allow for an evidence-based
method of creating a standardized protocol for autologous serum
production. If the results of these studies also demonstrate the
benefit of autologous serum, then in the words of Dr. Stephen
Pflugfelder, autologous serum really would be a tonic for the
ailing corneal epithelium.
Cornea
73
References
1. Chen YM, Hu FR, Huang JY, et al. The effect of topical autologous
serum on graft re-eptihelialization after penetrating keratoplasty.
Am J Ophthalmol. 2010; 150:352-359.
14. Noda-Tsuruya T, Asano-Kato N, Toda I, Tsubota K. Autologous

serum eye drops for dry eye after LASIK. J Refract Surg. 2006;
22:61-66.
2. Chiang CC, Chen WL, Lin JM, et al. Allogeneic serum eye drops
for the treatment of persistent corneal epithelial defect. Eye 2009;
23:290-293.
15. Ogawa Y, Okamoto S, Mori T, et al. Autologous serum eye drops

for the treatment of severe dry eyes in patients with chronic graftversus-host disease. Bone Marrow Transplant 2003; 31:579-583.
3. Esquenazi S, He J, Bazan HE, Bazan NG. Use of autologous serum

in corneal epithelial defects post-lamellar surgery. Cornea 2005;
24:992-997.
16. Pflugfelder SC. Is autologous serum a tonic for the ailing corneal
epithelium? Am J Ophthalmol. 2007; 142:316-317.
4. Fox R, Chan R, Michelson J, et al. Beneficial effect of artificial tears

made with autologous serum in patients with keratoconjunctivitis
sicca. Arthritis Rheum. 1984; 27:459-461.
5. Geerling G, MacLennan S, Hartwig D. Autologous serum eyedrops
for ocular surface disorders. Br J Ophthalmol. 2004; 88:14671474.
6. Goto E, Shimmura S, Shimazaki J, et al. Treatment of superior
limbic keratoconjunctivitis by application of autologous serum.
Cornea 2001; 20:807-810.
7. Jeng BH, Dupps WD. Autologous serum 50% eyedrops in the treatment of persistent corneal epithelial defects. Cornea 2009; 28:11041108.
8. Kojima T, Ishida R, Dogru M, et al. The effect of autologous serum
eyedrops in the treatment of severe dry eye disease: a prospective
randomized case-control study. Am J Ophthalmol. 2005; 139:242246.
9. Lee GA, Chen SX. Autologous serum in the management of recalcitrant dry eye syndrome. Clin Exp Ophthalmol. 2008; 36:119-122.
10. Liu L, Hartwig D, Harloff S, et al. An optimized protocol for the
production of autolgous serum eyedrops. Graefes Arch Clin Exp
Ophthalmol. 2005; 243:706-714.
11. Matsumoto Y, Dogru M, Goto E, et al. Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology
2004; 111:1115-1120.
12. McDonnell PJ, Schanzlin DJ, Rao NA. Immunoglobulin deposition
in the cornea after application of autologous serum. Arch Ophthalmol. 1988; 106:1423-1425.
13. Noble BA, Loh RSK, MacLennan S, et al. Comparison of autologous serum eye drops with conventional therapy in a randomised
controlled crossover trial for ocular surface disease. Br J Ophthalmol. 2004; 88:647-652.
17. Poon AC, Geerling G, Dart JKG, et al. Autologous serum eyedrops
for dry eyes and epithelial defects: clinical and in vitro toxicity studies. Br J Ophthalmol. 2001; 85:1188-1197.
18. Ralph RA, Doane MG, Dohlman CH. Clinical experience with a
mobile ocular perfusion pump. Arch Ophthalmol. 1975; 93:10391043.
19. Schulze SD, Sekundo W, Kroll P. Autologous serum for the treatment of corneal epithelial abrasions in diabetic patients undergoing
vitrectomy. Am J Ophthalmol. 2006; 142:207-211.
20. Tsubota K, Goto E, Fujita H, et al. Treatment of dry eye by autologous serum application in Sjgrens syndrome. Br J Ophthalmol.
1999; 83:390-395.
21. Tsubota K, Goto E, Shimmura S, et al. Treatment of persistent
corneal epithelial defect by autologous serum application. Ophthalmology 1999; 106:1984-1989.
22. Weisbach V, Dietrich T, Kruse FE, et al. HIV and hepatitis B/C
infections in patients donating blood for use as autologous serum
eye drops. Br J Ophthalmol. 2007; 91:1724-1725.
23. Yoon KC, Heo H, Im SK, et al. Comparison of autologous serum
and umbilical cord serum eye drops for dry eye syndrome. Am J
Ophthalmol. 2007; 144:86-92.
24. Young AL, Cheng ACO, Ng HK, et al. The use of autologous
serum in persistent corneal epithelial defects. Eye 2004; 18:609614.
25. Ziakas NG, Boboridis KG, Terzidou C, et al. Long-term follow up
of autologous serum treatment for recurrent corneal erosions. Clin
Exp Ophthalmol. 2010; 38:683-687.
74
Cornea
Whats New in the Genetics of Fuchs Dystrophy?

2. Specific genes
I. Introduction
Fuchs endothelial corneal dystrophy (FCD) is a common condition. The hallmark of the disease, cornea
guttata, is present in about 5% of the population over
age 40 in the United States.1 According to the Eye
Bank Association of America, corneal edema due to
FCD was the most common indication among the
approximately 42,000 corneal transplants performed
in the United States in 2009, accounting for over 9900
grafts.2 FCD also may have been a contributing factor among many of the 12,800 additional procedures
performed for postcataract surgery corneal edema or
repeat transplants for failed grafts.
Despite the frequency of the disease and our extensive
knowledge of the natural history and surgical treatment
of FCD, our understanding of the causes of FCD is limited. Prior investigators have identified proteins, genes,
genetic loci, and microstructural findings that implicate
biochemical pathways and mechanisms of disease,
but a unifying theory of disease pathogenesis is lacking. Without further understanding of the root causes
of FCD, discovering treatments other than surgical
replacement of diseased endothelial tissue will remain
elusive.
The purpose of this presentation is to provide a review
of our current knowledge of the possible causes of
FCD, with a focus upon recent genetic discoveries.
II. Understanding the Mechanisms of Disease
a. Transcription factor 4 (TCF4)8

b. Transcription factor 8 (ZEB1)6
c. SLC4A113
IV. Proteins and Pathways
A. Antioxidant pathways
1. Oxidative stress as a mechanism of FCD makes
sense.
a. Interpalpebral cornea (which has greatest
exposure to UV light) more involved than
periphery.
b. Aqueous very high in citrate, an antioxidant
endothelium from FCD corneas more susceptible to oxidative stress
2. Proteins implicated
a. Peroxiredoxins: Decreased in FCD9
b. DJ-1 (Jurkunas et al, abstract #6469, ARVO
2011)
i. a cofactor in the production of antioxidants
ii. decreased in FCD
B. Glycolysis
A. Genetics
Decreased levels of glycolytic enzymes (Hecker et al,

abstract #6599, ARVO 2011)
B. Proteins
1. -enolase
C. Biochemical pathways
2. PGK-1
D. Cellular microstructure
C. Transcription factors
E. Environmental associations / modifiable risk factors

III. Genetics
1. E2-2 protein (TCF4 gene)

2. ZEB1 (aka zinc finger E-box binding homeobox
1, transcription factor 8)
A. Early-onset FCD
1. Distinct from common older-onset FCD
2. Mutations in col8A23: alpha 2 chain of collagen
8
D. Other proteins
1. Clusterin
a. Elevated in FCD
b. Nonspecific stress protein
B. Older onset FCD
2. SLC4A11
1. Chromosomal loci
a. Chr. 5q33.1-q35.24
a. Sodium boron cotransporter
b. Chr. 13pTel-13q12.135
b. Unknown mechanism of action
c. Chr.
96
18q21.2-q21.327:
d. Chr.
mon association
May be most com-
c. Implicated in small percentage of FCD families
Cornea
V. Microstructural Abnormalities
A. Guttae: May implicate abnormal collagen production
B. Endoplasmic reticulum
4. Paradox of replication studies of TCF4/

Fuchs11,12
a. Fuchs associated with SNP rs613872 in TCF4
gene.
stress10
b. TCF4 variant not predictive of affected vs.

unaffected within families.
1. Unfolded protein response

2. May lead to apoptosis
c. Linkage studies map to chr. 18 region separate from TCF4.
VI. TCF4 gene (E2-2 protein)

A. General information
1. helix-loop-helix proteins: Dimerize to serve as
promoters or inhibitors of DNA transcription
2. Ubiquitous proteins that serve numerous functions: Important in differentiation and development as well as ongoing cellular processes
3. Corresponds to chromosome 18 locus
B. E2-2 in various tissues
1. Responsible for Pitt-Hopkins syndrome
a. Mental retardation
b. Periodic hyperventilation / apnea
VII. ZEB1
A. Recognized role in cornea disease
1. Posterior polymorphous dystrophy
2. Congenital hereditary endothelial dystrophy
3. One family with FCD6
B. General information
1. aka Zinc finger e-box homeobox 1, transcription
factor 8, TCF8
2. A transcription factor
3. Plays integral role in EMT
a. Transcription factor
c. Seizures
b. Implicated in other dystrophies
2. Tumor suppressor effect: Inhibitor of cyclin

dependent kinase pathway via p21cip1
i. posterior polymorphous dystrophy

ii. congenital hereditary endothelial dystrophy
3. Tumor promoter via epithelial to mesenchymal

transition (EMT)
C. E2-2 and EMT
1. EMT
EMT is a complex pathway controlling the balance between cells expressing epithelial vs. mesenchymal characteristics.
a. Epithelial characteristics: cell polarity, basement membrane, intercellular adhesion, noninvasive
b. Mesenchymal characteristics: loss of polarity,
loss of adhesion, invasive nature
c. E-cadherin is marker and regulator of EMT.
2. E2-2 represses e-cadherin.
D. E2-2 and Fuchs
1. Found by genome-wide association study and
confirmed in replication8,11,12
2. Role in FCD is unknown.
3. Possible roles
a. Regulation of gene transcription and thus
expression of proteins such as antioxidants
b. Maintenance of tissue phenotype via EMT
c. Numerous other possibilities
75
VIII. SLC4A113
A. Na+-borate co-transporter protein: Cellular function uncertain
B. Mutations of SLC4A11
1. Likely an uncommon cause of FCD
2. FCD mechanism may be accumulation of misfolded protein.
References
1. Lorenzetti DW, Uotila MH, Parikh N, Kaufman HE. Central cornea guttata: incidence in the general population. Am J Ophthalmol.
1967; 64:1155-1158.
2. America EBAo. 2009 Eye Banking Statistical Report. Washington,
DC.
3. Vithana EN, Morgan PE, Ramprasad V, et al. SLC4A11 mutations
in Fuchs endothelial corneal dystrophy. Hum Mol Genet. 2008;
17:656-666.
4. Riazuddin SA, Eghrari AO, Al Saif A, et al. Linkage of a mild lateonset phenotype of Fuchs corneal dystrophy to a novel locus at
5q33.1-q35.2. Invest Ophthalmol Vis Sci. 2009; 50:5667-5671.
5. Sundin OH, Jun AS, Broman KW, et al. Linkage of late-onset Fuchs
corneal dystrophy to a novel locus at 13pTel-13q12.13. Invest
6. Riazuddin SA, Zaghloul NA, Al-Saif A, et al. Missense mutations
in TCF8 cause late-onset fuchs corneal dystrophy and interact with
FCD4 on chromosome 9p. Am J Hum Genet. 2010; 86:45-53.
76
7. Sundin OH, Broman KW, Chang HH, Vito EC, Stark WJ, Gottsch
JD. A common locus for late-onset Fuchs corneal dystrophy maps
to 18q21.2-q21.32. Invest Ophthalmol Vis Sci. 2006; 47:39193926.
8. Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchss
corneal dystrophy. N Engl J Med. 2010; 363:1016-1024.
9. Jurkunas UV, Rawe I, Bitar MS, et al. Decreased expression of
peroxiredoxins in Fuchs endothelial dystrophy. Invest Ophthalmol
Vis Sci. 2008; 49:2956-2963.
10. Engler C, Kelliher C, Spitze AR, Speck CL, Eberhart CG, Jun AS.
Unfolded protein response in Fuchs endothelial corneal dystrophy:
a unifying pathogenic pathway? Am J Ophthalmol. 2010; 149:194202.
11. Li YJ, Minear MA, Rimmler J, et al. Replication of TCF4 through
association and linkage studies in late-onset Fuchs endothelial corneal dystrophy. PLoS One. 2011; 6:e18044.
12. Riazuddin SA, McGlumphy EJ, Yeo WS, Wang J, Katsanis N,
Gottsch JD. Replication of the TCF4 intronic variant in late-onset
Fuchs corneal dystrophy and evidence of independence from the
FCD2 locus. Invest Ophthalmol Vis Sci. 2011; 52:2825-2829.
Cornea
Cornea
77
Future Therapies for Corneal Endothelial Disease

The corneal endothelium, which is located at the innermost

layer of the cornea, plays a crucial role in maintaining corneal
transparency via its barrier and pump functions. The human
corneal endothelium is generally nonregenerative in vivo; thus
the corneal endothelial cell loss due to Fuchs corneal endothelial
dystrophy, corneal trauma, and surgical intervention such as
cataract surgery, etc. is followed by an enlargement of the adjacent endothelial cells. However, if corneal endothelial cell loss
is too severe, the cornea develops an irreversible corneal endothelial dysfunction. Although either penetrating keratoplasty,
Descemet-stripping automated endothelial keratoplasty, or Descemet membrane endothelial keratoplasty has been the choice of
surgery for recovering visual loss due to corneal endothelial dysfunction, a massive corneal endothelial cell loss postoperatively
can be a long-term problem following the procedures described
above.
To overcome these problems and to achieve a sophisticated
treatment, we must develop new surgical and medical therapeutic modalities for corneal endothelial disease, which provide a
healthy corneal endothelium with high cell density. To achieve
this we have been currently focusing on the basic understanding
and clinical application of cell proliferation and migration process of human corneal endothelial cells both in vitro and in vivo.
Figure 1. Future therapies for corneal endothelial disease.
Our recent attempts to develop new therapeutic modalities

for corneal endothelial disease are divided into 3 approaches as
follows:
1. Cultivated corneal endothelial cell sheet transplantation
2. Cultivated corneal endothelial cell injection therapy
3. Eye drops
Generally, the proliferative ability of corneal endothelial cells
in primates and humans is severely limited; we have been developing a new cultivating method of promoting cell proliferation
with good physiological function. This procedure is applicable to
the human corneal endothelium as well.
lial dysfunction. A corneal endothelial cell sheet transplantation with cells grown on a type I collagen carrier was successful
to some extent, but a good material for the cell carrier has to be
developed.
Figure 2. Cultivated human corneal endothelium.
Cultivated Corneal Endothelial Cell Injection

Therapy3
A recent report described that the Rho-kinase (ROCK) inhibitor,
Y-27632, promotes cell adhesion and proliferation and inhibits
the apoptosis of primate corneal endothelial cells in culture.
When cultivated corneal endothelial cells in rabbits and monkeys
were injected into the anterior chamber in the presence of ROCK
inhibitor, endothelial cell adhesion was enormously promoted,
resulting in the achievement of a high cell density with a normallooking morphology. Therefore, a cell-injection therapy combined with the application of ROCK inhibitor may be a promising procedure in the future.
Eye Drops4
We are also trying to develop a novel medical treatment for the
early phase of corneal endothelial disease by the use of ROCK
inhibitor eye drops. In rabbit and monkey experiments using partial endothelial dysfunction models, corneal endothelial wound
healing was accelerated by the topical application of ROCK
inhibitor to the eye, resulting in the regeneration of a corneal
endothelial monolayer with a high endothelial cell density. We
are now trying to establish 1 clinical trial for patients with partial
corneal endothelial dysfunction.
References
Cultivated Corneal Endothelial Cell Sheet
Transplantation1,2
We described the results of cultivated corneal endothelial cell
sheet transplantation in primates for advanced corneal endothe-
1. Koizumi N, Sakamoto Y, Okumura N, Okahara N, Tsuchiya H,

Torii R, Cooper LJ, Tanioka H, Kinoshita S. Cultivated corneal
endothelial cell sheet transplantation in a primate model. Invest
78
2. Koizumi N, Sakamoto Y, Okumura N, Tsuchiya H, Torii R, Cooper LJ, Ban Y, Tanioka H, Kinoshita S. Cultivated corneal endothelial transplantation in a primate: possible future clinical application in corneal endothelial regenerative medicine. Cornea 2008;
suppl.:48-55.
3. Okumura N, Ueno M, Koizumi N, Sakamoto Y, Hirata K, Hamuro
J, Kinoshita S. A ROCK inhibitor enhances survival of primate
corneal endothelial cells in vitro. Invest Ophthalmol Vis Sci. 2009;
50:3680-3687.
4. Okumura N, Koizumi N, Ueno M, Sakamoto Y, Takahashi H,
Hirata K, Torii R, Hamuro J, Kinoshita S. Enhancement of corneal
endothelium wound healing by a Rho-associated kinase (ROCK)
inhibitor eye drop. Br J Ophthalmol. 2011; 95:1006-1009.
Cornea
Cornea
79
How the Cornea Remains Clear in Health and Disease

Dimitri T Azar MD
Outline
I. Corneal Clarity
A. Corneal endothelium as a barrier to aqueous humor
B. Corneal endothelium as a metabolic pump
II. Corneal Avascularity
A. The balance of angiogenic and anti-angiogenic factors in the cornea
B. The limbus and the limbal barrier: Questionable
role in corneal angiogenic privilege
III. Loss of Corneal Clarity
A. Diseases associated with loss of corneal clarity
B. Pathophysiology
C. Treatment options
IV. Loss of Corneal Avascularity
A. Diseases associated with corneal neovascularization
B. Pathophysiology
C. Treatment Options
Corneal Clarity and Avascularity

Corneal clarity and corneal avascularity are important for the
proper optical performance of the cornea. Approximately 1 mm
thick peripherally and 0.5 mm centrally, the cornea comprises an
outer stratified squamous nonkeratinized epithelium, an inner
connective tissue stroma with resident keratocytes, and bordering the anterior chamber, a low cuboidal endothelium. Corneal
avascularity is an active process involving the production of antiangiogenic factors, which counterbalance the proangiogenic/lymphangiogenic factors that are upregulated during wound healing.
Balance of Angiogenic and Anti-angiogenic Factors in

the Cornea
Corneal neovascularization (NV) in response to tissue injury,
resulting from trauma, infection, and inflammatory or degenerative disorders, involves the dual invasion of blood (hemangiogenesis) and lymphatic (lymphangiogenesis) vessels. More often,
corneal wound healing occurs in the absence of NV. In this situation, the balance between angiogenic factors, such as fibroblast
growth factor-2 (FGF-2) and vascular endothelial growth factor
(VEGF), and anti-angiogenic molecules, such as angiostatin,
endostatin, or pigment epithelium-derived factor (PEDF), is
tilted toward anti-angiogenesis. Corneal angiogenic privilege and
maintenance of corneal avascularity occur not only as a result
of the upregulation of anti-angiogenic factors but also from the
downregulation of pro-angiogenic factors.
In healthy corneas after minor injury, the upregulation of
anti-angiogenic factors tilts the balance toward vessel regression.
Following corneal wound healing, newly formed vessels do not
invade the cornea, which maintains corneal avascularity. This

can be attributed to the upregulation of anti-angiogenic factors
and/or to a decrease in angiogenic factors, resulting in a shift
toward vessel regression. While not much research has been published on this topic, vessel regression following corneal wound
healing is likely due to a combination of anti-angiogenic factor
upregulation and angiogenic factor downregulation.
The Limbus and the Limbal Barrier

The limbus is believed to play an integral role in preventing corneal NV and maintaining corneal avascularity. The limbal barrier hypothesis is one of the most well-accepted explanations for
the mechanism behind the limbal anti-angiogenic effect and the
severe NV seen in limbal deficiency and damage. This hypothesis
describes the constant renewal (proliferation, migration, and differentiation) of corneal epithelial cells by the limbus as acting as
a physical barrier to prevent conjunctival and vessel outgrowth
in the cornea. However, the concept of the limbus acting as a
physical barrier to prevent corneal NV has been recently questioned.
In our laboratory, we have used a bFGF pellet corneal NV
model to demonstrate that the limbus may not necessarily function as a true physical barrier to NV. Our results showed that
removal of half of the limbus (hemilimbal deficiency) leads to
corneal NV from the opposite side of the cornea where the limbus was intact; this observation questions the role of the limbus
and whether it truly acts as a physical barrier to corneal NV.
Since it has long been believed that the role of the limbus in
corneal NV was to act as a true physical barrier, inhibiting the
growth of vessels, additional studies in this area are required to
elucidate the role of the limbus in corneal angiogenic privilege.
Diseases Associated With Loss of Corneal Clarity

Corneal edema
The corneal endothelium maintains corneal clarity through 2
functions: by acting as a barrier to the aqueous humor and by
providing a metabolic pump. Alteration of either function by
damage or maldevelopment leads to corneal edema, a condition
of abnormal homeostasis resulting in excess fluid within the corneal stroma and/or epithelium.
Various traumatic, inflammatory, and dystrophic mechanisms can produce corneal edema, such as trauma, inflammation, hypoxia, hydrops from ruptured Descemet membrane,
increased IOP, Fuchs dystrophy, posterior polymorphous dystrophy, iridocorneal endothelial syndrome, and retained lens
fragment.
Diseases Associated With Corneal NV

A wide variety of insults can tip the balance between angiogenic
and anti-angiogenic factors in favor of angiogenesis and cause
various patterns of NV. Processes of corneal NV can be caused
by inflammatory disorders, corneal graft rejection, infectious
80
keratitis, contact lensrelated hypoxia, alkali burns, neurotrophic ulceration, aniridia, and limbal stem cell deficiency. NV
patterns can generally be grouped into 3 clinical entities: (1)
deep NV overlying the Descemet membrane, as seen in herpetic
and luetic interstitial keratitis, (2) stromal NV, which is mainly
associated with stromal keratitis, and (3) vascular pannus composed of connective tissue proliferating in the superficial corneal
periphery and mainly associated with ocular surface disorders.
References
1. Ellenberg D, Azar DT, Hallak JA, et a.. Novel aspects of corneal
angiogenic and lymphangiogenic privilege. Prog Retin Eye Res.
2010; 29(3):208-248.
2. American Academy of Ophthalmology. Basic and Clinical Science
Course Section 8: External Disease and Cornea. Chapter 1: Structure and function of the external eye and cornea. San Francisco:
AAO; 2011-2012, p. 3.
Cornea
81
Cornea
Financial Disclosure
The Academys Board of Trustees has determined that a

financial relationship should not restrict expert scientific,
clinical, or nonclinical presentation or publication, provided
that appropriate disclosure of such relationship is made. As
an Accreditation Council for Continuing Medical Education
(ACCME) accredited provider of CME, the Academy seeks to
ensure balance, independence, objectivity, and scientific rigor in
all individual or jointly sponsored CME activities.
All contributors to Academy educational activities must disclose any and all financial relationships (defined below) to the
Academy annually. The ACCME requires the Academy to disclose the following to participants prior to the activity:
r BOZLOPXOGJOBODJBMSFMBUJPOTIJQTBNFFUJOHQSFTFOUFS
author, contributor, or reviewer has reported with any
manufacturers of commercial products or providers of
commercial services within the past 12 months
r BOZNFFUJOHQSFTFOUFS BVUIPS DPOUSJCVUPS PSSFWJFXFS
(hereafter referred to as the Contributor) who report
they have no known financial relationships to disclose
For purposes of this disclosure, a known financial relationship is defined as any financial gain or expectancy of financial
gain brought to the Contributor or the Contributors family,
business partners, or employer by:
r EJSFDUPSJOEJSFDUDPNNJTTJPO
r PXOFSTIJQPGTUPDLJOUIFQSPEVDJOHDPNQBOZ
r TUPDLPQUJPOTBOEPSXBSSBOUTJOUIFQSPEVDJOHDPNQBOZ
even if they have not been exercised or they are not
DVSSFOUMZFYFSDJTBCMF
r GJOBODJBMTVQQPSUPSGVOEJOHGSPNUIJSEQBSUJFT JODMVEJOH
research support from government agencies (e.g., NIH),
EFWJDFNBOVGBDUVSFST BOEPSQIBSNBDFVUJDBMDPNQBOJFT
or
r JOWPMWFNFOUJOBOZGPSQSPGJUDPSQPSBUJPOXIFSFUIF
Contributor or the Contributors family is a director or
recipient of a grant from said entity, including consultant
fees, honoraria, and funded travel.
The term family as used above shall mean a spouse,
domestic partner, parent, child or spouse of a child, or a brother,
sister, or spouse of a brother or sister, of the Contributor.
Category
Code
Description
$POTVMUBOU"EWJTPS
$
$POTVMUBOUGFF QBJEBEWJTPSZ
boards or fees for attending a
meeting (for the past one year)
Employee
Employed by a commercial
entity
Lecture fees
Lecture fees (honoraria), travel

fees or reimbursements when
speaking at the invitation of a
commercial entity (for the past
one year)
&RVJUZPXOFS
0
&RVJUZPXOFSTIJQTUPDLPQUJPOT
of publicly or privately traded
firms (excluding mutual funds)
with manufacturers of commercial ophthalmic products or
commercial ophthalmic services
1BUFOUT3PZBMUZ
1
1BUFOUTBOEPSSPZBMUJFTUIBU
might be viewed as creating a
potential conflict of interest
Grant support
Grant support for the past one

year (all sources) and all sources
used for this project if this form
is an update for a specific talk
or manuscript with no time
limitation
82
2011 Cornea Planning Group Financial Disclosures
Alcon Laboratories, Inc.: L
Allergan, Inc.: C,L
Bausch + Lomb Surgical: L
EyeGate Pharma: C
Inspire Pharmaceuticals, Inc.: C,L
3BQJE1BUIPHFO4DSFFOJOH 0
Vistakon Johnson & Johnson Visioncare, Inc.: L
National Eye Institute: S
3FTFBSDIUP1SFWFOU#MJOEOFTT 4
Anthony J Aldave MD
Allergan, Inc.: C
Michael W Belin MD
Allergan, Inc.: L
Oculus, Inc.: C,L
David B Glasser MD
None
Donald Tan MD FRCS FRCOphth

Bausch + Lomb Surgical: C
Carl Zeiss Meditec: L
NetWork Medical Products: P
Santen, Inc.: L
AAO Staff
Ann LEstrange
None
Melanie Rafaty
None
Debra Rosencrance
None
Cornea
83
Cornea
Faculty Financial Disclosures
Roy S Chuck MD PhD

Alcon Laboratories, Inc.: C

IOP: C
University of California: P
Abbott Medical Optics: C,L

Alcon Laboratories, Inc.: C,L
Hoya Corp.: C,L
Otsuka Pharmaceutical Co.: C,L
Pfizer, Inc.: C,L
Santen, Inc. C,L
Senju Paharmaceutical Co.: C,L
Anthony J Aldave MD
Allergan, Inc.: C
Bausch + Lomb Surgical: S

Johnson & Johnson Consumer &
Personal Products Worldwide: S

Allergan, Inc.: C,S
Bausch + Lomb Surgical: C,S
Eleven Biotherapeutics: C,O
InSite Vision, Inc.: C
Pfizer, Inc.: C,S
3JHFM $
4JSUSJT(4, $ 4
Randy J Epstein MD
Addition Technology: C,L,S

Alcon Laboratories, Inc.: C,L,S
Allergan, Inc.: C,L,S
Aton, Inc.: C,L,S
Bausch + Lomb Surgical: C,L,S
Johnson & Johnson Consumer &
Personal Products Worldwide: L
Novartis Pharmaceuticals Corp.: C,L,S
Paragon Vision Sciences: C,L,S
Pfizer, Inc.: C,L,S
Santen, Inc.: C,L,S
Vistakon Johnson & Johnson
Visioncare, Inc.: C,L,S

Tear Sciences, Inc.: C
Thomas M Lietman MD
Per Fagerholm MD
None
None
Marjan Farid MD
Francis S Mah MD
None
Alcon Laboratories, Inc.: C,S

Allergan, Inc.: C,S
Foresight Biotherapeutics: C
Inspire Pharmaceuticals, Inc.: C,S
Ista Pharmacuticals: C
Ocular Therapeutix: C
Ox-danthia: C,S
Dimitri T Azar MD
Allergan, Inc.: C,L
Bausch + Lomb Surgical: C
ForSight Labs: C
Prism Ventures: C
Sarentis: C
Kenneth M Goins MD
None
Jose Gomes MD
Allergan, Inc.: C,L
Fapesp, Brazil: S
Natura, Inc.: C
Anna S Kitzmann MD
None
Friedrich E Kruse MD
Cell Seed: C
Santen, Inc.: C
None

None
Stephanie Jones Marioneaux MD
None
None
Majid Moshirfar MD
None

3FTFBSDIUP1SFWFOU#MJOEOFTT *OD 4
Allergan, Inc.: C,L

Stuart I Brown MD
Bennie H Jeng MD
None
Santen, Inc.: C
Rudy Nuijts MD
Alan N Carlson MD
Alcon Laboratories, Inc.: L,S

Asico: P
Inspire Pharmaceuticals, Inc.: L

Tear Science: O

,FSB.FE *OD -
Ocular Therapeutix, Inc.: L
3FWJTJPO0QUJDT -
Seros Medical, USA: L
WaveLight AG: L

Allergan, Inc.: C
National Eye Institute: C,S
Kohji Nishida MD
None
84
Faculty Financial Disclosures
Abbott Medical Optics: C,L

Addition Technology: C
Allergan, Inc.: C,L
Calhoun Vision, Inc.: O
Cellular Bioengineering, Inc.: C
Forsight Vision: C
Inspire Pharmaceuticals, Inc.: C
Ista Pharmacuticals: C
Moria: L
Oculus, Inc.: C
OPHTEC, BV: C,L
3F7JUBM7JTJPO 0
TearLab: O
Voisin Consulting: C

Allergan, Inc.: C,L
Bausch + Lomb Surgical: L
EyeGate Pharma: C
3BQJE1BUIPHFO4DSFFOJOH 0
Visioncare, Inc.: L
None
Accutome: C
Allergan, Inc.: C,L,
Inspire Pharmaceuticals, Inc.: L
,BUFOB1SPEVDUT *OD $
,POBO $
4IBSQQPJOU"OHJPUFDI 4
Visioncare, Inc.: L
Geoffrey C Tabin MD
None
Mark A Terry MD
Bausch + Lomb Surgical: P
Optovue: O
Cornea
Cornea
Presenter Index
Aquavella*, James V 56
Asbell*, Penny A 63
Azar*, Dimitri T 79
#BSBU[ ,FJUI)VHI
Brown, Stuart I 55
Carlson*, Alan N 51
Chodosh*, James 1
$IVDL 3PZ4
%BOB 3F[B
&QTUFJO 3BOEZ+
'BHFSIPMN 1FS
'BSJE .BSKBO
(PJOT ,FOOFUI.
(PNFT +PTF
)BNNFSTNJUI ,SJTUJO.
Huang*, Andrew J W 61
Jeng*, Bennie H 71
,BOFMMPQPVMPT "+PIO
,JOPTIJUB 4IJHFSV
,JU[NBOO "OOB4
,SVTF 'SJFESJDI&
Lietman, Thomas M 26
Liu, Christopher 3
.BI 'SBODJT4
Margolis, Todd P 33
.BSJPOFBVY 4UFQIBOJF+POFT
Moshirfar, Majid 66
/JTIJEB ,PIKJ
/VJKUT 3VEZ
1SBKOB /7FOLBUFTI
1SJDF 'SBODJT8
3PTFOXBTTFS (FPSHF0%
Sangwan, Virender S 21
5BCJO (FPGGSFZ$
Terry*, Mark A 35

85

AAO - Cornea - 2011-Consensus and Controversies

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AAO - Cornea - 2011-Consensus and Controversies

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Subspecialty Day

In conjunction with the Cornea Society

2011 Cornea Planning Group

Subspecialty Day Advisory Committee

Donald L Budenz MD MPH

2011 Subspecialty Day

2011 Subspecialty Day |

Cornea 2011 Contents

Program Directors Welcome Letter ii

Ocular Surface DiseaseReplacement vs. Regeneration 1

Corneal TransplantationLamellar Keratoplasty 35

Corneal TransplantationPenetrating Keratoplasty and Pediatric Keratoplasty 49

Ocular Surface DiseaseTherapeutics 58

2011 Subspecialty Day

Academys CME Mission Statement

2011 Cornea Subspecialty Day Meeting Learning

2011 Cornea Subspecialty Day Meeting Target

2011 Cornea Subspecialty Day CME Credit

Scientific Integrity and Disclosure of Relevant

has mechanisms in place to resolve all conflicts of interest prior

Attendance Verification for CME Reporting

CME Credit Reporting

2011 Subspecialty Day |

Penny A Asbell MD FACS

James Chodosh MD MPH

Keith Hugh Baratz MD

2011 Subspecialty Day

Roy S Chuck MD PhD

Sao Paulo, SP, Brazil

Reza Dana MD MSc MPH

Andrew J W Huang MD MPH

2011 Subspecialty Day |

Christopher Liu FRCOphth

Todd P Margolis MD PhD

2011 Subspecialty Day

Stephanie Jones Marioneaux MD

Maastricht, Limburg, Netherlands

Salt Lake City, UT

Virender S Sangwan MBBS

2011 Subspecialty Day |

Salt Lake City, UT

2011 Subspecialty Day

Cornea 2011: Controversies and Consensus

SATURDAY, OCTOBER 22, 2011

REGISTRATION/ MATERIAL PICKUP/ CONTINENTAL BREAKFAST

Welcome and Introductions

Ocular Surface DiseaseReplacement vs. Regeneration

Christopher J Rapuano MD*

Moderator: Anthony J Aldave MD*

The Boston Keratoprosthesis in the Management of Limbal Stem Cell

James Chodosh MD MPH*

The Osteo-Odonto-Keratoprosthesis for Management of Severe Ocular

Christopher Liu FRCOphth

A Biosynthetic Alternative to Human Donor Tissue

Oral Mucosal Epithelial Transplantation for the Management of Ocular

Cultivated Limbal Epithelial Transplantation for the Management of

Virender S Sangwan MBBS

Ocular Surface Reconstruction With Immature Dental Pulp Stem Cell

Jose Gomes MD*

Bacterial Keratitis: Synergy, Steroids, and Other Treatment Controversies

An Evidence-Based Approach to Managing Fungal Keratitis

N Venkatesh Prajna MD*

Corneal Collagen Crosslinking: Does It Have a Role in Managing

A John Kanellopoulos MD*