Developing Endothelial Keratoplasty: A Personal Journey Mark A. Terry, MD Director, Corneal Services Devers Eye Institute Scientific Director Lions VisionGift Research Lab Research Lab Portland, Oregon, U.S.A. Christian Ophthalmology Society August 5 th, 2016

Disclosures Bausch and Lomb Surgical: Royalty on instruments used in DSAEK (but not DMEK) and Educational grant for EKG meeting each year Moria: Educational grant for EKG meeting each year Off-Label Use: – Trypan blue – SF6 gas – Straiko-Jones glass tube (Straiko DMEK Injector)

The Ideal Keratoplasty Healthy donor endothelium Optically pure cornea Stable corneal power and astigmatism Globe safe from injury and infection Surgical technique is quickly and easily learned Terry MA. Endothelial Keratoplasty: Clinical Outcomes in the two years following deep lamellar endothelial keratoplasty. (An AOS Thesis)Trans Am Ophthalmol Soc 2007; 105:

The previous “Standard” was full thickness Penetrating Keratoplasty (PK) Unpredictable topography: high, irregular astigmatism, ametropia Suture related infections and graft rejections Weak wound – ruptures from minor trauma Disadvantages of traditional PK

The Revolution in Corneal Transplantation: Selective Endothelial Replacement From DLEK to DSAEK to DMEK Talajic JC, Straiko MD, Terry MA. An overview of endothelial keratoplasty. In: Expert Techniques in Ophthalmology. Chapter

Major Contributors to EK Development: Other Major Contributors (not pictured): Mark Gorovoy, Massimo Busin, Donald Tan, Mike Straiko, Edfel Yoeruek, Ken Goins, George Rosenwasser, B.J. Dupps, Tony Aldave, Rajesh Fogla and many more… Charles Tillet Lecturers

The evolution of Endothelial Keratoplasty DLEK: Hand dissected donor placed in a hand resected bed DSAEK: Microkeratome donor placed on a smooth stripped surface DMEK: Stripped Descemet’s placed on a smooth stripped surface

Our Current experience with over 2,600 cases of EK surgery from March 2000 to May 2016 (Prospective IRB Study) We developed and performed the first EK procedure in North America: 275 cases of DLEK (9mm and 5 mm inc) Over 1,700 cases of DSAEK >600 cases DMEK (first case in 2010) DMEK is now our preferred method of EK for routine cases Our Cornea Fellow each year performs between 90 and 100 DMEK Procedures (start to finish), about 20 complex DSAEK cases, and about 15 to 20 DALK cases; but only 25 PK cases

PK had been around for 100 years So how did a revolutionary procedure like EK become standard of care around the world in only 16 years time? Where does a “big idea” come from? How does it evolve? What is the background story? History of EK

THE HIDDEN HISTORY OF ENDOTHELIAL KERATOPLASTY -- Old forgotten publications and presentations -- Personal back-rounds only talked about over beers

First Successful Human EK: AJO 1956 Charles Tillet, M.D. from Wilmer Eye Inst A manual flap technique Of accessing posterior stroma (USING ONLY LOOPS – No Microscope!)

Charles Tillet, M.D. Wilmer Eye Institute 2010

Updated alternative procedure: Automated “Flap” Technique of EK: First described by Barraquer, with later animal experiments by Pollock and others (1950’s and 60’s) Late 1990’s: First microkeratome use for “flap technique” described separately by Culbertson (“ELK”) and Busin (“Endokeratoplasty”) and Azar (“Microkeratome assisted PLK”),

“Flap” Technique of EK: Advantages: familiar, automated instrumentation and relative ease of surgery Disadvantages: Still retained the same liabilities of PK: --Surface sutures (for the flap) --Unstable wound --Irregular astigmatism Added disadvantage of usual Lasik Flap problems were also encountered This “flap technique” of EK was ultimately abandoned due to high rate of complications and poor visual results compared to DLEK.

First concept of a truly scleral-limbal approach to lamellar endothelial replacement which left the corneal surface untouched: 1993 Ko WW, Feldman ST, Frueh BE, Shields CK, Costello ML. “Experimental posterior lamellar transplantation of the rabbit cornea.” Invest Ophthalmol Vis Sci 1993; 34 (suppl): p Limbal Pocket created then Tissue sutured into pocket with mattress suture

: Gerrit R. J. Melles, M.D., PhD. Breakthrough innovation: Air bubble support of tissue eliminating sutures Cadaver eye work showed excellent topography Animal work showed healthy tissue donor endothelium after air bubble attachment Melles, GR, Eggink, FA, Lander F, et al. A surgical technique for posterior lamellar keratoplasty. Cornea 1998; 17:

How did I get involved with EK development in private practice at Devers in Portland, OR? 1997: I joined an “instrument development advisory board” for Storz Instruments (Bausch and Lomb) to design new corneal instruments 1998: Mark Mannis (editor of CORNEA) invites me to write a “History of Lamellar Surgery” article for the 25th anniversary issue of journal CORNEA 1998: I started reading more extensively the history of corneal transplantation to garner ideas on further innovations for instruments and for the review article.

1998 WAS A TOUGH YEAR! Professional  Devers Eye Institute had a major re-organization of physicians and staff and high level of turmoil with near implosion of the institute Personal  My twin boys were born 3 months premature (1.3 Kg) and in the Neonatal ICU for 2 months My beloved son Nicholas was discharged with a diagnosis of Cerebral Palsy and a dismal prognosis

Nicholas and Charlie In Neonatal ICU At Emanuel The War Time saying goes: “There are no atheists in Foxholes” The same can be said about the Neonatal Intensive Care Unit

Cindy and I finally get the boys home Initial prayers answered, my boys made it home. But how to cope with the stress of premature twins, no sleep, and coming to terms of having a special needs child. ---Prayers to stop the anger of shattered expectations. ---Prayers for a diversion.

“God delivers, but not always in the way you think he will …” J. James Rowsey, MD 1985

My EK Epiphany Moment: December 8 th, 1998: 2:00 am feeding Picture of me holding boys and reading Journal here Melles, GR, Eggink, FA, Lander F, et al. A surgical technique for posterior lamellar keratoplasty. Cornea 1998; 17:

First steps: 1999 Contact Storz with drawings of prototype instruments based upon Melles’ animal article Identify challenges of Melles’ published PLK technique : Whole globe donors not available in U.S.; Posterior corneal resections completely under air were difficult to the extreme I worked in minor O.R. at night and weekends to further develop procedure with cadaver eyes. I had one part-time tech…and I had never even met Dr Melles

Mark A. Terry, M.D. Laboratory work: design of new instruments Introduction of artificial anterior chamber for preparation of donor tissue using Corneo-scleral Donors Introduction and demonstration of Healon viscoelastic to replace air for easier and safer recipient resections Redesign EK surgery and practice with countless cadaver eyes LONG process to write protocol and get IRB approval for prospective pt study Terry, MA, Ousley, PJ. Endothelial replacement without surface corneal incisions or sutures: topography of the deep lamellar endothelial keratoplasty procedure. Cornea 2001; 20:

DLEK Surgical Technique Recipient tissue removed Hand Dissected Donor Corneoscleral incision, deep corneal pocket, and endothelium excised Endothelium from posterior stromal disc removed from pocket Endothelium replaced without sutures, Surface topography with minimal change Diagram courtesy of Dr. Ayad Farjo

First Endothelial Keratoplasty in the United States (Second EK surgery in the world) March 2000

The Team Behind the First Endothelial Keratoplasty in the U.S. Mark Terry John Wilkins Paula Ousley 3 hour surgery…but successful…

Our DLEK Results: Better for the Patient than PK Visual rehabilitation in 2 months, not 2 years No RGP needed, often no spectacles 20/30-20/40, but only 8% achieved 20/20 Improved QoV Rejection reduced to 9% from 18% in PK Endothelial cell loss (ECL) comparable to PK Terry MA. Endothelial Keratoplasty: Clinical Outcomes in the two years following deep lamellar endothelial keratoplasty. Trans Am Ophthalmol Soc 2007; 105:

Despite my training over 70 visiting surgeons free of charge: Why did PLK/DLEK not become popular? Still Technically too difficult Manual dissection of donor by surgeon risked loss of tissue Interface limited vision to 20/50 initially No pre-cut tissue Time to do surgery too long and reimbursement too low.

So: from the Surgeon’s Perspective : Comparing DLEK to PK DLEK vs. PK Easier Faster Better Terry MA. Endothelial Keratoplasty: Clinical Outcomes in the two years following deep lamellar endothelial keratoplasty. Trans Am Ophthalmol Soc 2007; 105:

2004: Gerrit R. J. Melles, M.D., PhD. Breakthrough innovation: Melles describes technique which eliminates need for manual lamellar dissection of recipient by removing recipient Descemet’s only – he calls this “Descemetorhexis” PLK. Melles GR, Wijdh RH, Nieuwendaal, CP. A technique to excise the descemets’ membrane from a recipient cornea (descemetorhexis). Cornea :

Further modifications of Melles Descemetorhexis technique: Price: interface fluid removal techniques (DSEK) Gorovoy: Use of microkeratome for donor (DSAEK) Dislocation rate still too high (10% to 50%) Primary Graft Failure Rate too High(6% to 25%) Pupillary Block from air bubble with vision loss reported Kitsmann AS, Goins KM, Reed C, Padnick-Silver L, Macsai MS, Sutphin JE. Eye bank survey of surgeons using pre-cut donor tissue for Descemet’s stripping endothelial keratoplasty. Cornea 2008; 27: Persistent Problems with DSEK/DSAEK Persistent Problems with DSEK/DSAEK:

: Mark A. Terry, M.D. A Simplified, Standardized Technique Peripheral recipient bed scraping technique introduced to DSAEK to promote donor adherence Dislocation rate reduced to 1.5% (3 cases) in first consecutive 200 DSAEK cases 60/40 underfold to prevent upside-down grafts Primary Graft Failure reduced to 0% in 200 cases Smaller bubbles Pupillary Block: 0% in first 200 cases Terry MA, Hoar KL, Wall J, Ousley, PJ. The Histology of Dislocations in Endothelial Keratoplasty (DSEK and DLEK): Prevention of dislocation with a laboratory-based surgical solution in 100 consecutive DSEK cases. Cornea 2006; 25: Terry MA, et al: Endothelial Keratoplasty: A simplified technique to minimize dislocations, primary graft failure, and pupillary block. Ophthalmology 2008; 115:

DS(A)EK Surgical Technique Corneoscleral incision, endothelium STRIPPED from posterior cornea Endothelium with stroma replaced without sutures, surface topography minimally changed Hand-dissected donor DSEK Donor cut by Microkeratome DSAEK Images Courtesy of Dr. Ayad Farjo

Our Standardized DSAEK Surgery Since 2004

DSAEK: further advances that made EK more accepted Surgery was now vastly easier than DLEK Several of us (EBAA corneal surgeons) worked with the AAO to get a new code for “EK” transplant surgery approved for Medicare billing (HUGE issue!) Two eye banks in the U.S. (Lions Eye Bank of Oregon and North Carolina Eye Bank) learned to “pre-cut” donor tissue for transplantation, eliminating the risk to surgeons of this step of surgery

DSAEK Results: Better than DLEK and PK Visual rehabilitation in 1 month, not 2 months 18% achieved 20/20 Even better Quality of vision Rejection about the same Endo survival better than DLEK and PK Easier and More Secure for the Surgeon: – No deep corneal pocket dissection – Eye banks prepared tissue (and assumed the risk) – New EK CPT code Li JY, Terry MA, Goshe J, Davis-Boozer D, Shamie N. Three-year visual acuity outcomes after Descemet’s stripping automated endothelial keratoplasty. Ophthalmology 2012;119(6):

The Surgeon’s Perspective: DSAEK vs. PK or DLEK Easier Faster Better Terry MA. Endothelial Keratoplasty: Clinical Outcomes in the two years following deep lamellar endothelial keratoplasty. Trans Am Ophthalmol Soc 2007; 105:

And: DSAEK could be done for almost all forms of endothelial decompensation Pseudophakic Bullous Keratopathy Failed PK ICE CHED etc

First successful DSAEK in CHED Eyes in the United States: Devers ( Long term follow-up) Pre-op: CHED in 7 y/o girl Va cc = 20/200 OU Post-op at 6 years (pt is now 13 y/o: Va cc = 20/25- OU Goshe JM, Li JY, Terry MA. Successful DSAEK for congenital hereditary endothelial dystrophy in a pediatric patient. Int Ophthalmol Feb; 32(1): 61-6.

DSAEK in an 18 month old boy Pre-op OD: DSAEK for CHED Post-op 4 months: OD DSAEK

How is Devers Program in DSAEK doing? (N = first 800 Fuchs cases at Devers – 10 surgeons) Primary Graft Failure Rate: National: 5%Devers: <1% Graft Dislocation Rate: National: 15%Devers: 1.8% Endothelial cell loss at 6 months: National: 35%Devers: 22% Graft survival at 5 years: National: “who knows?” Devers: 97% (n=120)

Trends in Keratoplasty Image Courtesy of Eye Bank Association of America

What About DMEK? ( Descemet Membrane Endothelial Keratoplasty) Can we provide PURE anatomic replacement of the endothelium in a standardized procedure?

The evolution of Endothelial Keratoplasty DLEK: Hand dissected donor placed in a hand resected bed DSAEK: Microkeratome donor placed on a smooth stripped surface DMEK: Stripped Descemet’s placed on a smooth stripped surface

Primary reasons for learning DMEK Represents exact anatomic replacement EK (God knows best!) Better visual results than DSAEK Faster visual recovery than DSAEK Has a lower rejection rate than DSAEK (<1% in first two years)

Popularity of DMEK in the U.S. Total EK procedures in U.S. in 2015: 27,208 Total DSAEK cases: 22,514 Total DMEK cases: 4,694 EBAA MAB Statistics and Data Report 2015

Explosive Growth in DMEK: But absolute numbers very small compared to DSAEK 2015 EBAA Statistical Report

Explosive Growth in DMEK: But absolute numbers very small compared to DSAEK

The Surgeon’s Perspective: DMEK vs. DSAEK Easier Faster Better Terry MA. Endothelial Keratoplasty: Why aren’t we all doing DMEK? Cornea 2012; 31(5):

DMEK at Devers: Making it easier, faster and standardized Pre-stripped tissue from the Lions VisionGift S-Stamp provided by the eye bank Over-stripping of the recipient (Kruse) Straiko glass injector No bubble tap unfolding technique (Yoeruek) 20% SF6 bubble for postop donor support (Guell)

Devers Eye Institute Standardized DMEK with Phaco Terry MA, Straiko MD, Veldman PV, Talajic JC, VanZyl C, Sales CS, Mayko ZM. A standardized DMEK technique: Reducing complications using pre-stripped tissue, novel glass injector, and sulfer hexafluoride (SF6) gas. Cornea 2015;34(8):845-52

DMEK 3 weeks post-op: Vasc = 20/20+1 Talajic JC, Straiko MD, Terry MA. An overview of endothelial keratoplasty. In: Expert Techniques in Ophthalmology. Chapter

DSAEK and DMEK in same pt DMEK: Va = 20/20 at 2 monthsDSAEK: Va = 20/25 at 8 months OD OS Talajic JC, Straiko MD, Terry MA. An overview of endothelial keratoplasty. In: Expert Techniques in Ophthalmology. Chapter (in press)

1 st 100 Standardized DMEK vs. 1 st 100 Standardized DSAEK at DEI Hemzaoglu EC, Straiko MD, Mayko ZM, Sales CS, Terry MA. DSAEK vs. DMEK: First 100 eyes of each using a standardized technique at one institution. Ophthalmology Busin M et al: Ultra-thin DSAEK with microkeratome double pass technique. Ophthalmology. 2013; 120: * P <0.05 For DMEK vs. DSAEK * *

1 st 100 Standardized DMEK vs. 1 st 100 Standardized DSAEK at DEI Hemzaoglu EC, Straiko MD, Mayko ZM, Sales CS, Terry MA. DSAEK vs. DMEK: First 100 eyes of each using a standardized technique at one institution. Ophthalmology 2015 P=0.45 P=0.38

1 st 100 Standardized DMEK vs. 1 st 100 Standardized DSAEK at DEI Hemzaoglu EC, Straiko MD, Mayko ZM, Sales CS, Terry MA. DSAEK vs. DMEK: First 100 eyes of each using a standardized technique at one institution. Ophthalmology * P >0.05 * * *

You still need to be able to do DSAEK: When is DSAEK Preferable to DMEK? Prior vitrectomy Tubes and Trabs ACIOL ICE, aniridia Aphakia Veldman PB, Terry MA, Straiko MD. Evolving indications for Descemet’s stripping automated endothelial keratoplasty. Current Opinion in Ophthalmol. 2014;25:

The Uncertain Future of Endothelial Keratoplasty After all these breakthroughs in corneal transplantation, why uncertain? Now that we have exact anatomic replacement surgery, what could possibly be better?....

What’s Better? Surgery, but no transplant needed

Surgery without a transplant for Fuchs’ Corneal Dystrophy Randelman et al: Stripped central Descemet’s in one pt with PPMD and cornea cleared spontaneously Colby et al: Stripped 4.0 mm of central Descemet’s in pts with Fuchs and 10 of 13 corneas cleared spontaneously Koenig: Stripped 6.0 mm of central Descemet’s in two Fuchs eyes and the corneas did NOT clear Problems right now: 1.Takes weeks or months for corneas to clear…and no guarantee to clear 2.Final central cell counts end up very low

51 y/0 woman with 4 mm removal of Descemet’s only OD os Pre-op Post op 3 months Surgery and Photos courtesy of Kathryn Colby, M.D., PhD.

What’s Better? No surgery at all

Translational Research for Corneal Endothelial Regeneration Noriko Koizumi, M.D., Ph.D. and Shigeru Kinoshita, M.D.; PhD. Professor, Biomedical Engineering, Doshisha University, Kyoto, Japan Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan Taiwan Ophthalmological Society Session Advanced concepts for corneal endothelial therapy WOC 2014 Tokyo, April 3, 2014

OD VA=(20/20), CCT 570μm OS VA=(20/100), 703μm OD 632 cells/mm 2 OS (peripheral area) 757 cells/mm 2 * * * * * * * * * * * * * * * * * * * * * * * * * * Multiple guttae Central corneal edema with epithelial bullae 52-year-old male, Fuchs dystrophy Pilot clinical study of ROCK inhibitor for BK scheduled for DSAEK

52-year-old male, Fuchs dystrophy Transcorneal freezing (2mm area) Topical Therapy: ROCK inhibitor 10mM of Y-27632, 6 times/day, 7 days Pre-op central bullae

Pre-treatment 52-year-old male, Fuchs dystrophy VA=20/100, CCT=703μm 1M post-treatment VA=20/20, CCT=607μm

Pre-treatment Post-treatment (3 years) VA 20/20, CCT 568μm 3 years follow-up after ROCK inhibitor treatment Koizumi N (Okumura N, Kinoshita S). Rho-associated kinase (ROCK) inhibitor eye drop treatment as a possible medical treatment for Fuchs corneal dystrophy. Cornea, 32(8): , 2013

Summary and Conclusions The evolution of corneal transplantation over the past 16 years has been astonishing and our patients have benefited immensely DMEK represents pure anatomic replacement surgery and takes us as far as surgery can go. Standardization and surgical simplification of DMEK should now lead to full acceptance by transplant surgeons. Final thoughts for COS…

Final Thoughts The “Big Ideas” which become game changers in surgery (think phaco for cataract surgery, and EK for corneal transplants) rarely come out of prestigious universities, but usually from individual surgeons who are passionate about what they do and unhappy with the status quo. All of the “pioneers” in EK surgery have their own story. For me: God took a sad, angry, and sleep-deprived surgeon from the backwaters of Portland, OR and provided a powerful diversion. He instilled in me a passion to try and make a difference in my field. Through the grace of God, my field and my life, have been forever changed for the better.

CINDY THANK YOU CHARLIE NICHOLAS