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Risk factor Analysis for Long-term Outcome of Keratolimbal Allografts . Young Eun Lee, MD 1,2 , Eui Seok Han, MD 1,2 , Mee Kum Kim, MD 1,2 , Won Ryang Wee, MD 1,2. 1 Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea - PowerPoint PPT Presentation
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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
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
Patients and Methods
Recipient superficial
keratectomy
Symble-pharon dissec-
tion, if present
PKP or cataract
surgery, if required
Preparation of ring-shaped donor graft
(trephination and 1/3 thick-ness dissec-
tion)
Limbo-scle-ral side su-
ture with 8-0 Vicryl
Limbo-corneal side suture with 10-0 Nylon
Transient am-niotic mem-brane trans-plantation (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
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
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
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
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
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
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
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 KLAL 8 (62%) 16 (50%) 0.528
PKP 7 (54%) 14 (44%) 0.743
AMT 5 (38%) 10 (31%) 0.732Postoperative 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.
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.
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