Keratolimbal allograft

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Article initiated by:
Albert Y. Cheung
All contributors:
Shabnam Mansur, Colleen Halfpenny, M.D., Albert Y. Cheung
Assigned editor:
Neha Shaik, MD
Review:
Assigned status Update Pending
.


Introduction

Keratolimbal allograft (KLAL) is a type of ocular stem cell transplantation (OSST) that treats limbal stem cell deficiency (LSCD).

LSCD rises from a variety of etiologies, including but not limited to: aniridia, chemical burns, Stevens-Johnson syndrome, iatrogenic causes, and contact-lens-induced keratopathy. LSCD often causes poorly healing epithelial defects, stromal scarring, and conjunctivalization and neovascularization of the cornea. Patients subsequently experience diminished vision and ocular pain. There is also an increased risk of keratoplasty rejection/failure with total LSCD [1][2].

KLAL transplants allogenic limbal tissue attached to a corneoscleral carrier from a deceased donor. This option of ocular stem cell transplantation is ideal for patients with bilateral LSCD without a living donor or unilateral LSCD with an unaffected eye unsuitable as a donor. KLAL can also benefit patients with etiologies of LSCD that do not involve the conjunctiva, such as aniridia.

History

The first allograft procedure for severe ocular surface disease was described in 1984 by Thoft, which was coined keratoepithelioplasty[3]. This procedure used lenticules from the peripheral cornea of a deceased donor as the source of epithelium and did not utilize limbal cells. In 1990, Turgeon and colleagues, including Thoft, modified this technique to include limbal tissue[4]. This is the first recorded keratolimbal allograft procedure. Other early KLAL techniques were recorded by Tsai and Tseng in 1994[5], Tsubota in 1995[6], and Holland in 1996[7].

Indications

KLAL is an ideal OSST procedure for the following cases:

  • Bilateral LSCD without a related, matched, living donor
  • Unilateral LSCD where the unaffected eye is unsuitable for a conjunctival limbal autograft (i.e. prior contact lens use, ocular surgery, etc.)
  • LSCD that mainly involves the limbus with minimal to no conjunctival involvement (etiologies such as aniridia, contact-lens wear related LSCD, and iatrogenic)[1][2]

Contraindications

Relative contraindications to KLAL are severe, cicatrizing etiologies of LSCD. These etiologies include Stevens-Johnson Syndrome, mucous membrane pemphigoid, or severe chemical injury. Severe cases may decrease KLAL success secondary to chronic conjunctival inflammation and scarring, decreased mucin, aqueous tear deficiency, and increased potential for keratinization [7][8]. If KLAL is the only option, the eye should be quiet for at least one year prior to KLAL surgery to optimize graft survival. However, these cases generally are better suited to a combined KLAL with living-related conjunctival limbal allograft (KLAL/lr-CLAL) or combined KLAL with conjunctival limbal autograft (KLAL/CLAU) [9][10].

Medical contraindications to systemic immunosuppression are also a relative contraindication to any OSST procedure, as systemic immunosuppression is essential for long-term graft survival[11][12][13].

Donor Tissue Selection

Selection guidelines for high quality donor KLAL tissue include: [3][7]

  • Younger donors, preferably under 60 years of age
  • Minimal time from donor death to tissue preservation
  • Implantation of KLAL tissue within 5 days of donor death
  • Maintenance of conjunctiva (>3-4mm skirt) and more sclera (4-5mm) to allow for transplantation of goblet cells and minimization of stem cell damage
  • Corneoscleral rims from both eyes of the same donor to limit antigenic exposure to recipient
  • No active infection in donor
  • No prior ventilator exposure in donor
  • No prior history of metastatic cancer of melanoma in the donor [14]

Surgical Procedure & Technique

  1. Patient should be supine. General anesthesia or retrobulbar block.
  2. Perform 360-degree limbal peritomy.
  3. Recess conjunctiva at the limbus and excise symblephara.
  4. Remove the abnormal fibrovascular pannus and epithelium from the corneal surface to leave a smooth surface.
  5. Excise central cornea of 2 corneoscleral rims with a 7.5-8.0mm trephine. Section the remaining corneoscleral rim into equal halves.
  6. Dissect excess peripheral scleral tissue 2-3mm peripheral to the limbus with Westcott scissors.
  7. Use a crescent blade to remove the posterior half of each crescent (posterior stroma, Descemet’s membrane, and endothelium) by lamellar dissection to create 4 crescents, made from 2 corneoscleral rims.
    • Posterior lamellar dissection can be made easier with an assistant to stabilize the anterior part of the KLAL crescent.
    • Since only 3 of the crescents will typically be used, 1 extra crescent is present if needed. This can be positioned concentrically in correct anatomic orientation over the exposed bare sclera over areas to treat severe or recurrent symblephara. It can also be used for a patch graft if a perforation is encountered during superficial keratectomy.
  8. Taper the corneal edge of the crescent with Vannas scissors to allow the donor corneal edge to meet the recipient cornea without a sharp tissue edge. Failure to do this may decrease epithelization, as the epithelium may have difficulty migrating over such a sharp slope.
  9. Three crescents are placed around the recipient cornea with the anterior corneal edge overlying the recipient limbus. Secure the crescents with 10-0 nylon sutures.
    • Gaps between KLAL segments should be eliminated, as they can allow conjunctival cells to repopulate the corneal surface. Host and donor conjunctiva should be well approximated to each other, or the host conjunctiva should be slightly pulled over the donor conjunctiva. This avoids the possibility of host conjunctival growth under the grafts and prevents the formation of inclusion cysts.
  10. Tissue glue is used to secure the posterior aspect of each KLAL segment.
  11. Place a soft bandage contact lens (large diameter), protective patch, and eye shield[15][16][17][18].

There are several different techniques to prepare the donor tissue. Other techniques may involve mounting the donor tissue to allow for the dissection.

Post-operative period

  • Topical lifitegrast 5% or cyclosporine 0.05% should be continued twice daily for the life of the KLAL graft.
  • A topical fluoroquinolone is continued until corneal epithelium had healed and bandage-contact lens is removed.
  • Topical difluprednate is continued 3-4 times daily unless there is a corticosteroid intraocular pressure response. If IOP is elevated, decrease strength of corticosteroid to prednisolone acetate 1% or flurorometholone 0.1%.
  • An optical keratoplasty (penetrating keratoplasty or deep anterior lamellar keratoplasty) may be required to fully recover vision following successful KLAL.

Immunosuppression

Systemic immunosuppression is essential for ocular surface stability and long-term graft survival following KLAL.

The Cincinnati OSST Immunosuppression Protocol involves oral tacrolimus, mycophenolate mofetil, prednisone, and antimicrobials[13].

  • Oral tacrolimus (Prograf) 4 mg twice daily and oral mycophenolate mofetil (MMF; Cellcept) 1 g twice daily are initiated 1-2 weeks before surgery. Patients with adequate ocular surface stability are tapered off tacrolimus starting at 12-18 months postoperatively and MMF starting 3 years postoperatively.
  • Oral prednisone 1mg/kg daily is added following surgery, tapered over 1-3 months depending on level of postoperative inflammation.
  • Opportunistic infections are prevented by administering valganciclovir (Valcyte) and trimethoprim/sulfamethoxazole (TMP/SMX, single strength) every Monday, Wednesday, Friday for 3-6 months. Dapsone is a suitable alternative for patients with sulfa allergies.


Any history of graft rejection warrants maintenance of low-dose systemic immunosuppression indefinitely. It is recommended to involve an organ transplant specialist with experience with these medications in the care of KLAL patients[13].

Outcomes

The most important desired outcome after KLAL is a stable ocular surface, defined as an intact corneal epithelium with no conjunctivalization of the surface, neovascularization, or inflammation.

Graft failure is the absence of a stable ocular surface. Risk factors for KLAL graft failure include keratinization[7], dry eye [19], symblephara [20][21], chronic inflammation [22], prior rejection[23], lid abnormalities[24], preoperative increased intraocular pressure[12], and inflammatory etiologies such as SJS[17].

Several different categories of graft failure have been described.

  • Primary failure: Absence of primary corneal epithelialization with progressive epithelium loss over the KLAL within the first postoperative week.
  • Partial failure: Areas of healthy corneal epithelium interspersed with areas of conjunctivalization over the peripheral cornea with late staining.
  • Total failure: Recurrence of total LSCD.
  • Late failure: Partial/total failure attributed to chronic rejection in the absence of other causes.

The rates of ocular surface stability and graft failure after KLAL vary by study. The best outcomes have been from groups using a 3-agent systemic immunosuppression regimen.

  • Baradaran-Rafii et al. reported primary failure in 5 eyes out of 66 total KLALs. Primary failure resulted from ocular surface exposure, dry eye from SJS, and poor donor tissue quality. These eyes all underwent repeat KLAL. Due to late failure, 14 more eyes underwent repeat KLAL. At last follow-up, 33 out of 45 eyes (73.4%) maintained a stable ocular surface. [25]
  • Holland et al reported a stable ocular surface at last follow-up in 73% of 94 eyes with a mean follow-up of 4.7 years. An expanded cohort achieved ocular surface stability in 77% of 225 eyes over 4.5 years [13][26].

Complications

Acute immunologic rejection is the most common postoperative complication[25]. This can present as regional or 360 KLAL swelling and engorgement, moderate to severe conjunctival injection, ocular pain, and photophobia.

Chronic rejection is more insidious. This manifests as gradual surface failure (conjunctivalization/vascularization), graft thinning, and low-grade inflammation.

Rates of acute vs chronic rejection as well as severe vs low-grade rejection also vary by study.

  • Baradan-Rafii et al. reported 16 episodes of acute rejection in eight eyes. Four of these KLALs (25%) ultimately failed. Chronic rejection was reported in 24 eyes, and 8 of these KLALs (33.3%) ultimately failed. Acute rejection was treated with increased topical and systemic steroids and increased systemic immunosuppression. Chronic rejection was treated with increased systemic immunosuppression only[25].
  • Holland et al. categorized rejection based on clinical presentation and severity rather than time frame. 19.4% of eyes showed severe rejection and 11.7% showed low-grade rejection. Risk factors for immunologic rejection were younger age at transplantation, KLAL procedure alone (vs lr-CLAL or combination procedures), and noncompliance with immunosuppression. Eyes with a history of rejection had a worse final outcome (39% with a stable ocular surface) compared to those without rejection (72% stable ocular surface). Notably, fewer low-grade rejections compared to severe rejections resolved with medical treatment[13][26].


All patients with any severity of rejection should be treated aggressively with increased topical and systemic immunosuppression. Consider extending the course of systemic immunosuppression if signs of rejection manifest[27]. Alongside increased systemic immunosuppression, Holland et. al use topical difluprednate 0.05% hourly, 1-2 weeks of high-dose oral prednisone tapered over several weeks [23]. There is also evidence that intravenous immunoglobulin (IVIG) may treat acute antibody-mediated KLAL rejection. Squissato et al. presented one case of a patient that developed graft rejection 2 weeks after KLAL despite optimal systemic immunosuppression. IVIG therapy led to immediate symptomatic improvement and a stable corneal epithelium at fifteen months after KLAL[28].

Other non-rejection-related complications of KLAL include recurrent symphlepara [29] increased risk of infectious keratitis secondary to persistent epithelial defects in the setting of systemic infection, and glaucoma secondary to an underlying etiology of LSCD or secondary to long-term corticosteroid use postoperatively[8].

References

  1. ↑ 1.0 1.1 Haagdorens, M., et al., Limbal Stem Cell Deficiency: Current Treatment Options and Emerging Therapies. Stem Cells Int, 2016. 2016: p. 9798374.
  2. ↑ 2.0 2.1 Cheung, A.Y., et al., Limbal Stem Cell Deficiency: Demographics and Clinical Characteristics of a Large Retrospective Series at a Single Tertiary Referral Center. Cornea, 2021.
  3. ↑ 3.0 3.1 Thoft RA. Keratoepithelioplasty. Am J Ophthalmol 1984; 97:1-6.
  4. ↑ Turgeon PW, Nauheim RC, Roat MI, et al. Indications for keratoepithelioplasty. Arch Ophthalmol 1990; 108:233-236.
  5. ↑ Tsai RJ, Tseng SC. Human allograft limbal transplantation for corneal surface reconstruction. Cornea 1994; 13(5):389-400.
  6. ↑ Tsubota K, Toda I, Saito H, et al. Reconstruction of the corneal epithelium by limbal allograft transpltation for severe ocular surface disorders. Ophthalmology 1995;102:1486-1495.
  7. ↑ 7.0 7.1 7.2 7.3 Holland EJ. Epithelial transplantation for the management of severe ocular surface disease. Trans Am Ophthalmol Soc 1996; 94:677-743.
  8. ↑ 8.0 8.1 Chan CC, Holland EJ. Keratolimbal allograft. In: Holland EJ, Mannis MJ, Lee WB, editors. Ocular surface disease: cornea, conjunctiva and tear film. New York: Elsevier; 2013. pp. 341–346.
  9. ↑ Biber JM, Skeens HM, Neff KD, et al. The cincinnati procedure: technique and outcomes of combined living-related conjunctival limbal allografts and keratolimbal allografts in severe ocular surface failure. Cornea 2011; 30:765– 771.
  10. ↑ Chan CC, Biber JM, Holland EJ. The modified Cincinnati procedure: combined conjunctival limbal autografts and keratolimbal allografts for severe unilateral ocular surface failure. Cornea 2012; 31:1264–1272.
  11. ↑ Holland EJ, Djalilian AR, Schwartz G. Management of aniridic keratopathy with keratolimbal allograft: a limbal stem cell transplantation technique. Ophthalmology 2003; 110:125–130.
  12. ↑ 12.0 12.1 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; 127:1428–1434.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 Holland EJ, Mogilishetty G, Skeens HM, et al. Systemic immunosuppression in ocular surface stem cell transplantation: results of a 10-year experience. Cornea 2012; 31:655–661.
  14. ↑ Holland E, LoVerde L. Conjunctival limbal melanoma after a keratolimbal allograft. Paper Presentation at Eye Bank Association of America Fall Educational Symposium, Chicago, IL 2016.
  15. ↑ Croasdale CR, Schwartz GS, Malling JV, et al. Keratolimbal allograft: recommendations for tissue procurement and preparation by eye banks, and standard surgical technique. Cornea 1999; 18:52–58.
  16. ↑ Daya SM, Holland EJ, Mannis MJ. Living-related conjunctival limbal allograft. In: Holland EJ, Mannis MJ, editors. Ocular surface disease. New York: Springer; 2002. pp. 201–207.
  17. ↑ 17.0 17.1 Schwartz GS, Tsubota K, Tseng SCG, et al. Keratolimbal allograft. In: Holland EJ, Mannis MJ, editors. Ocular surface disease. New York: Springer; 2002. pp. 208–222.
  18. ↑ Nassiri N, Pandya HK, Djalilian AR. Limbal allograft transplantation using fibrin glue. Arch Ophthalmol 2011; 129:218–222.
  19. ↑ Shimazaki J, Shimmura S, Fujishima H, et al. Association of preoperative tear function with surgical outcome in severe Stevens–Johnson syndrome. Ophthalmology 2000; 107:1518–1523.
  20. ↑ Ilari L, Daya SM. Long-term outcomes of keratolimbal allograft for the treat- ment of severe ocular surface disorders. Ophthalmology 2002; 109:1278– 1284.
  21. ↑ Han ES, Wee WR, Lee JH, et al. Long-term outcome and prognostic factor analysis for keratolimbal allografts. Graefes Arch Clin Exp Ophthalmol 2011; 249:1697 – 1704.
  22. ↑ Samson CM, Nduaguba C, BaltatzisS , et al.Limbal stem cell transplantation in chronic inflammatory eye disease. Ophthalmology 2002; 109:862–868. 20.
  23. ↑ 23.0 23.1 Ang AY, Chan CC, Biber JM, et al. Ocular surface stem cell transplantation rejection: incidence, characteristics, and outcomes. Cornea 2013; 32:229– 236.
  24. ↑ DeSousa JL, Daya S, Malhotra R. Adnexal surgery in patients undergoing ocular surface stem cell transplantation. Ophthalmology 2009; 116:235– 242.
  25. ↑ 25.0 25.1 25.2 Baradaran-Rafii A, Eslani M, Djalillian AR. Complications of keratolimbal allograft surgery. Cornea 2013; 32:561–566.
  26. ↑ 26.0 26.1 Holland EJ, Schwartz GS. The Paton lecture: ocular surface transplantation: 10 years’ experience. Cornea 2004; 23:425–431.
  27. ↑ Eslani M, Haq Z , Movahedan A , et al. Late acute rejection after allograft limbal & stem cell transplantation: evidence for long-term donor survival. Cornea 2017;36:26 – 31.
  28. ↑ Squissato V, Schiff J, Chan CC. Intravenous immunoglobulin for antibody- & mediated keratolimbal allograft rejection. BMJ Case Rep 2015; 2015:. IVIG may be used in combination with systemic immunosuppression to treat acute antibody-mediated KLAL rejection; it may be useful to test for donor-specific antibodies after severe rejection.
  29. ↑ Farid M, Lee N. Ocular surface reconstruction with keratolimbal allograft for the treatment of severe or recurrent symblepharon. Cornea 2015; 34:632–636.
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