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Young Eun Lee, MD 1,2 , Eui Seok Han, MD 1,2 , Mee Kum Kim, MD 1,2 , Won Ryang Wee, MD 1,2 Risk factor Analysis for g-term Outcome of Keratolimbal Allograf 1 Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea 2 Laboratory of corneal regenerative medicine and ocular immunology, Seoul Artificial Eye Center, Seoul National University Hospital Clinical Research Institute, Seoul, Korea The authors have no financial interest in the subject matter of this poster

Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

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Page 1: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Young Eun Lee, MD1,2, Eui Seok Han, MD1,2, Mee Kum Kim, MD1,2, Won Ryang Wee, MD1,2

Risk factor Analysis for Long-term Outcome of Keratolimbal Allografts

1Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea

2Laboratory of corneal regenerative medicine and ocular immunology, Seoul Artificial Eye Center, Seoul National University Hospital

Clinical Research Institute, Seoul, Korea

The authors have no financial interest in the subject matter of this poster

Page 2: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Introduction & Purpose

Keratolimbal allograft (KLAL)

• Several successful short-term reports in the 1990s1-4

• Long-term results were not satisfactory.5,6

• Survival of KLAL: 23.7%/21.2% at 5 years (2002 reports)5,6

Several conditions influencing KLAL success7-11

• Chronic conjunctival inflammation• Tear film deficiency• Symblepharon• Rejection

Because there have been few documented studies on a large number of KLAL patients, the impor-tant prognostic factors influencing KLAL success are unknown.

So, we retrospectively reviewed our cases to elucidate the prognostic factors for KLAL success and the long-term outcomes of KLAL in our series over 10-year period.

Pupose

Page 3: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Patients and Methods

Recipient su-perficial kera-

tectomy

Symblepharon dissection, if

present

PKP or cataract

surgery, if re-quired

Preparation of ring-shaped donor graft

(trephination and 1/3 thick-ness dissec-

tion)

Limbo-scleral side suture with 8-0 Vicryl

Limbo-corneal side suture with 10-0 Nylon

Transient amni-otic membrane transplantation

(AMT)

24 eyes of 22 patients• Partial or total KLAL surgery• From 2000 to 2009• Follow-up ≥ 1 year• Limbal deficiency diagnosis

Corneal vascularization orConjunctivalization orPersistent epithelial defect orGoblet cell on the corneal surface

Patients

Surgical procedures

Page 4: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Patients and Methods

If, REJECTION

• Delayed epithelialization: full epithelialization after 2 months postoperatively

• Infectious keratitis: proved when culture (+)• Increased intraocular pressure (IOP) ≥ 21mmHg• Graft failure:

Corneal vascularization orConjunctivalization orPersistent epithelial defect orGoblet cell on the corneal surface

If rejection,• Oral CSA ↑ or add MMF 1g bid• Oral Corticosteroid ↑• Corticosteroid eyedrop ↑

Postoperative care Rejection care

Immunosuppression

• Corticosteroid 30mg/day for 2weeks• Cyclosporin A (CSA) 2.5~5.0mg/kg for 6 months/

dose-adjustment for 100~150ng/ml trough level• Mycophenolate mofetil (MMF) 1g bid in high-risk

Ocular care • Ofloxacin• Corticosteroid• Autoserum• Artificial tears• Therapeutic contact lens

Definition of complications

Page 5: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Patients and Methods

KLAL success

• No persistent epithe-lial defect

• No conjunctivalization• No neovascularization

PKP success

• No corneal opacity• No Persistent, irre-

versible rejection

Best corrected vis-ual acuity (BCVA)

• Before surgery• After surgery• Last follow-up

Primary failure

• Refractory corneal ep-ithelial defect

• Irreversible rejection

Demographics

• Age• Gender

Diagnosis

• Stevens Johnson syn-drome (SJS)

• Chemical burn• Others

Previous history

• Graft rejection• KLAL• PKP

Concurrent surgery

• Partial or total KLAL• PKP• AMT

Preoperative state

• BCVA ≥ 0.1 or not• Lid deformity• Conjunctival inflam-

mation• High IOP• Symblepharon

Postoperative state

• Initial CSA dose• High IOP • Epithelialization

within 2 months• Interval for full ep-

ithelialization

Clinical outcome evaluation Prognostic factor evaluation

Page 6: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Patients and Methods

Clinical outcome evaluationStatistics of prognostic factor

Evaluation of KLAL survival

Kaplan-Meier survival curve

Statistically significance

Multivariate analysis

Cox proportional hazards survival regression

Univariate analysis

Chi-square test Mann-Whitney U test

P < 0.10

P < 0.05

Page 7: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Result (Clinical outcome)

Patients characteristics• M:F (17:5), 24 eyes of 22 patients• Age: 39.4 ± 17.4 years• Follow-up: 47.3 ± 22.0 months (17-114)• Diagnosis

SJS 6

Chemical burn 5

Others 13• Total KLAL: 46 times (1 outside)• Simultaneous PKP: 11 eyes

• Delayed epithelialization: 3 eyes (5months on average)• Newly developed epithelial defect: 8 (33.3%)• Increased IOP: 9 (37.5%), 6 medically controlled.• Corneal melting: 2 (8.3%)• Bacterial keratitis: 3 • Fungal keratitis: 1• Herpetic keratitis: 1

KLAL failure (n=16, 66.7%)

• Primary failure 3 (12.5%)• Persistent epithelial defect 8 (33.3%)• Conjunctivalization 4 (16.6%)• Corneal neovascularization 7 (29.2%)

PKP failure (n=7, 63.6%)

• Corneal opacity by limbal insufficiency 5 (45.5%)• Irreversible rejection with opacity 2 (18.2%)

Reversibility of KLAL and PKP rejection

• Only KLAL rejection: 6 eyes (all reversible)

• Only PKP rejection: 5 eyes (all reversible)

• KLAL+PKP rejection: 4 eyes (2 irreversible)

Patients Causes of KLAL & PKP failure

RejectionsComplications

Page 8: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Result (Clinical outcome and survival)

Repeated KLAL

Rapid decline until postoperative 10

months

SJS: Stevens-Johnson syndromeCB: chemical burnO: others

114 months

Long-term survival (+) after KLAL once

Postoperative months

Page 9: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Result (Clinical outcome and survival)

A B C

FED

Postoperative BCVA means the BCVA at the

last follow-up, which was almost the same or better than preoperative BCVA

KLAL failure (Ocular cicatrical pemphigoid)

KLAL success (thermal burn)

Preop 1 month 4 months

Preop 1 month 4 months

Postoperative months

Page 10: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Result (Prognostic factor analysis)

KLAL success (n=13)

KLAL failure (n=32) P valuea(b)

Demographics and diagnosis

Age (year) 43.5±16.7 37.3±17.4 0.316

Gender (Male) 11 (85%) 19 (59%) 0.165

Diagnosis

SJS 2 11

0.433Chemical burn 3 5

Others 8 16

Previous history of

Graft rejection 2 (22%) 3 (23%) 1.000

PKP 5 (38%) 8 (25%) 0.473

KLAL 6 (46%) 16 (50%) 1.000

Preoperative state

BCVA ≥ 0.1 3 (23%) 5 (15%) 0.672

Lid deformity 3 (23%) 20 (63%)0.023

(0.244)

Conjunctival inflammation

7 (54%) 26 (81%)0.076

(0.109)

High IOP 0 (0%) 3 (9%) 0.546

Symblepharon 2 (15%) 23 (72%)0.001

(0.010)c

KLAL success (n=13)

KLAL failure (n=32)

P valuea (b)

Concurrent surgery

Partial KLAL8 (62%) 16 (50%) 0.528

PKP7 (54%) 14 (44%) 0.743

AMT5 (38%) 10 (31%) 0.732

Postoperative data

Initial CSA dose 2.5mgd 2 (15%) 7 (26%) 0.690

High IOP within 1week

6 (55%) 13 (50%) 1.000

Epithelializa-tion within 2

months13 (100%) 20 (63%)

0.010 (0.737)

Interval for full epithelialization

(day)10.4±12.3 36.8±46.9

0.004 (0.858)

PKP = penetrating keratoplasty; BCVA = best corrected visual acuity; IOP = intraocu-lar pressure; AMT = amniotic membrane transplantation; CSA = cyclosporine A.

aUnivariate analysis was performed using the chi-square or Mann-Whitney U test. bVariables which were associated with risk of KLAL failure on univariate analysis (p<0.1) were analyzed in the multivariate Cox regression survival model. c95% confidence interval:0.016-0.563. dInitial CSA dose was 5.0mg/kg daily in usual.

Page 11: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Discussion

• The overall success of KLAL was 33.3% at 4 years, which is similar to two previous re-ports of the long-term outcome of KLAL.5-6 Our study included a relatively high portion of pa-tients with SJS and OCP (37.5%), which are known to lead to a relatively poor outcome.11

• Simultaneous PKP and KLAL were performed because of the limited availability of donor corneal tissues. The success of PKP was highly dependent on the success of KLAL, because grafted cornea often becomes opaque due to persistent epithelial defect or neo-vascularization following KLAL failure.

• Our KLAL rejection rate was 41.7% with strong systemic immune suppression, lower than the 87.5% in eyes with CSA alone6 but higher than the 17% rate in eyes receiving mycophe-nolate mofetil and tacrolimus.7

• All the rejection in KLAL alone was reversible, whereas concurrent rejection in both KLAL and PKP was irreversible in half cases. A more potent combination of immunosuppres-sants should be considered in concurrent KLAL/PKP rejection.

Page 12: Young Eun Lee, MD 1,2, Eui Seok Han, MD 1,2, Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Mee Kum Kim, MD 1,2, Won Ryang Wee, MD 1,2 Risk factor Analysis

Discussion

• Preoperative symblepharon is the most significant prognostic factor. – Forniceal contracture usually leads to frequent falling off of the contact lens, resulting in an unstable surface.– Combining lid entropion due to shortage of the fornix induces surface irritation and epithelial erosion..

• Limitations – It is a retrospective study and has limited variable factors that could not be controlled– The protocol of immunosuppressant administration and the surgeon’s skill likely changed over 9 years.

1. Thoft RA. The role of the limbus in ocular surface maintenance and repair. Acta Ophthal-mol Suppl. 1989;192:91-94.2. Tsai RJ, Tseng SC. Human allograft limbal transplantation for corneal surface reconstruc-tion. Cornea. 1994;13(5):389-400.3. Tan DT, Ficker LA, Buckley RJ. Limbal transplantation. Ophthalmology. 1996;103(1):29-36.4. Tsubota K, Toda I, Saito H, Shinozaki N, Shimazaki J. Reconstruction of the corneal ep-ithelium by limbal allograft transplantation for severe ocular surface disorders. Ophthalmol-ogy. 1995;102(10):1486-1496.5. Tsubota K, Satake Y, Ohyama M, et al. Surgical reconstruction of the ocular surface in ad-vanced ocular cicatricial pemphigoid and Stevens-Johnson syndrome. Am J Ophthalmol. 1996;122(1):38-52.6. Solomon A, Ellies P, Anderson DF, et al. Long-term outcome of keratolimbal allograft with or without penetrating keratoplasty for total limbal stem cell deficiency. Ophthalmology. 2002;109(6):1159-1166.7. Ilari L, Daya SM. Long-term outcomes of keratolimbal allograft for the treatment of severe ocular surface disorders. Ophthalmology. 2002;109(7):1278-1284.

8. Liang L, Sheha H, Tseng SC. Long-term outcomes of keratolimbal allograft for total limbal stem cell deficiency using combined immunosuppressive agents and correction of ocular surface deficits. Arch Ophthalmol. 2009;127(11):1428-1434.9. Maruyama-Hosoi F, Shimazaki J, Shimmura S, Tsubota K. Changes observed in kera-tolimbal allograft. Cornea. 2006;25(4):377-382.10. Samson CM, Nduaguba C, Baltatzis S, Foster CS. Limbal stem cell transplantation in chronic inflammatory eye disease. Ophthalmology. 2002;109(5):862-868.11. Shimazaki J, Shimmura S, Fujishima H, Tsubota K. Association of preoperative tear func-tion with surgical outcome in severe Stevens-Johnson syndrome. Ophthalmology. 2000;107(8):1518-1523.12. Tsubota K, Satake Y, Kaido M, et al. Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation. N Engl J Med. 1999;340(22):1697-1703.

In conclusion, KLAL has been partly successful for reconstruction of limbal stem cell deficiency, and symblepharon has been identified as a significant

prognostic factor for KLAL survival