Living-related conjunctival limbal allograft (lr-CLAL)

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


Introduction

Living-related conjunctival limbal allograft (lr-CLAL) 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 (SJS), contact-lens-induced keratopathy, and iatrogenic mechanisms. LSCD often causes poorly healing epithelial defects, stromal scarring, conjunctivalization, and neovascularization of the cornea. Patients subsequently experience diminished vision, ocular pain, and keratoplasty rejection.[1][2]

Lr-CLAL transplants allogenic limbal and conjunctival tissue with goblet cells from a matched living relative. This option of ocular stem cell transplantation is ideal for patients with bilateral LSCD or unilateral LSCD where the fellow eye is a poor donor. Unlike keratolimbal allografts (KLAL), lr-CLAL provides fresh conjunctiva in addition to limbal tissue. This makes lr-CLAL an optimal procedure for cases of LSCD with accompanying conjunctival disease.

History

Kenyon and Rapoza described the first lr-CLAL procedure in 1995, which they termed limbal allograft transplantation. Prior to this, no study had utilized limbal tissue with a conjunctival carrier from a living donor, alongside systemic immunosuppression (cyclosporine A, in this case) to prevent graft rejection [3][4]. Since then, others have developed donor-recipient matching processes to select the best donor to minimize antigenic exposure and graft rejection [5]. Cheung et al demonstrated lr-CLAL had lower rejection rates, improved graft survival, and better BCVA compared with KLAL[6].

Indications

Lr-CLAL is an ideal OSST procedure for the following cases:

  • Bilateral LSCD
  • Unilateral LSCD where the unaffected eye is unsuitable as a donor for a conjunctival limbal autograft (i.e. history of contact lens use, ocular surgery, etc.)
  • LSCD that involves deficiency/disease of the conjunctiva

Contraindications

Relative contraindications to lr-CLAL include significant conjunctival inflammation and scarring, significantly decreased mucin, aqueous tear deficiency, and ocular surface keratinization. These conditions have a poor prognosis with OSST. However, lr-CLAL has also shown potential to stabilize the ocular surface in these cases by providing limbal and conjunctival stem cells where prior KLAL has failed [7].

Medical contraindications to systemic immunosuppression are also a relative contraindication to any OSST procedure, as systemic immunosuppression is essential for long-term graft survival [8].

Preoperative considerations

Prior to lr-CLAL, the ocular surface should be optimized by addressing eyelid malposition, significant symblepharon, and trichiasis. Uncontrolled glaucoma must be managed preoperatively.

For chemical injuries, it is recommended to wait at least 12 months following the injury to allow the ocular surface to stabilize prior to lr-CLAL. If there is significant conjunctival inflammation and scarring, a combination OSST may be more suitable (see below) [9].

Donor Selection

Proper donor selection is crucial to maximize the success of lr-CLAL. By identifying the best possible donor candidate, one can minimize the antigenic burden and subsequent graft rejection. The Cincinnati donor selection protocol is currently the most detailed protocol for confirming potential lr-CLAL donors. This protocol begins with selecting a first-degree relative donor and conducting ABO blood typing. Panel reactive antibody (PRA) and donor-specific antibody (DSA) testing is also obtained. If the donor is still compatible following these steps, human leukocyte antigen (HLA) typing and virtual crossmatch is performed. Serologic testing for HIV I/II, hepatitis A/B/C, and cytomegalovirus is conducted prior to approving the donor and proceeding with lr-CLAL [10].

Donor eyes should also be carefully examined for subtle stem cell deficiency (i.e. late fluorescein staining). There cannot be a history of long-term contact lens wear or significant ocular surface disease, including prior surgery or trauma [10].

Lr-CLAL donor eyes are unlikely to develop ocular surface complications postoperatively [9]. Induction of LSCD in the donor eye may be prevented by harvesting 2 to 2.5 clock hours of limbal stem cells per conjunctival-limbal segment, with a total amount harvested less than 5 clock hours[10].

Surgical Procedure and Techniques

1. Harvesting the lr-CLAL Donor Segment

  1. Outline the conjunctival grafts (about 2 clock hours in limbal circumference or about 6 to 6.25 mm) at the 12- and 6-o’clock positions. Ensure the total tissue to be harvested is less than half the circumference (i.e. less than 6 clock hours).
  2. Elevate the conjunctiva from Tenon’s capsule/sclera with balanced salt solution (BSS)
  3. Dissect the graft by incising along the lateral borders and undermining with blunt Westcott scissors. Continue dissection posteriorly about 5 mm and 8mm for the 6-o’clock and 12-o’clock segments, respectively, and cut the posterior border of the graft.
  4. Reflect the conjunctiva anteriorly over the cornea, then continue blunt dissection to a point 1 mm onto the cornea (beyond the limbus) to ensure inclusion of the stem cells.
  5. Once the tissue is free, transfer it into BSS.
  6. After retrieval of both lr-CLAL segments, partially close the conjunctival defect with two 10-0 nylon sutures, with care not to pull the distal conjunctiva taut.
  7. Place a large diameter bandage contact lens.

2. Preparation of the Recipient Eye

  1. Perform a 360° conjunctival peritomy at the limbus, release symphlephara.
  2. Allow the conjunctiva to recess 2 to 3 mm from the limbus. This usually occurs naturally secondary to release of conjunctival tension.
  3. Tenon’s capsule (often thickened from inflammation) can be liberally excised, with care taken to preserve the overlying conjunctiva. In the presence of excess conjunctiva, a conservative amount may be trimmed. Topical epinephrine (1:10,000 dilution) and wet-field cautery may be needed for hemostasis.
  4. Remove abnormal corneal epithelium and fibrovascular pannus, taking care to avoid cutting deep into stroma.
  5. Amniotic membrane may be placed over the ocular surface to aid epithelization and decrease inflammation.

3. Placement of the Donor Tissue

  1. Suture the harvested lr-CLAL segments to the 12-o’clock and 6-o’clock positions at the limbal edge using two 10-0 nylon sutures cut short.
  2. Apply tissue glue to secure the base of the lr-CLAL tissue segments to the recipient sclera.
  3. Place a large diameter soft bandage contact lens.

Combination OSST Procedures

Lr-CLAL combined with another OSST procedure may be required if significant conjunctival inflammation and scarring exists.

  • The Cincinnati Procedure (KLAL/lr-CLAL): Ideal for bilateral cases of severe cicatrizing conjunctival disease and total limbal deficiency, such as SJS, mucous membrane pemphigoid, and certain severe chemical injuries. Lr-CLAL segments are placed at 12-o’clock and 6-o’clock while KLAL tissue is used to fill the remaining limbal areas at 3-o’clock and 9-o’clock [11]. This additional KLAL tissue prevents invasion of blood vessels and conjunctiva for nearly 360°, compared to 180°.
  • Lr-CLAL/CLAU: Ideal for severe unilateral concomitant limbal and conjunctival disease. This procedure may maximize the amount of healthy transplanted limbal stem cells and conjunctiva while minimizing antigenic burden. All transplanted tissue can potentially be a complete or near-complete HLA match (i.e. if a sibling donor is a complete HLA match)[12]. Additional tissue is placed at the 3-o’clock and 9-o’clock positions. However, this may not completely provide stem cells for 360° as with the Cincinnati Procedure.

Immunosuppression

Systemic immunosuppression is absolutely essential for ocular surface stability and long-term graft survival following lr-CLAL, even with high levels of HLA compatibility between donors and recipients.

The Cincinnati OSST Immunosuppression Protocol involves oral tacrolimus, mycophenolate mofetil, prednisone, and prophylactic antimicrobials [8].

  • 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) for 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 lr-CLAL patients [8].

Outcomes

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

Epithelization of the ocular surface typically occurs over 1-5 weeks, most frequently by 2-3 weeks. The rates of ocular surface stability after lr-CLAL vary by study and cohort.

  • In larger cohorts (≥10 eyes) comprised of mostly chemical injuries or mixed etiologies, ocular surface stability was achieved in 45% to 92% of eyes [13][14][15][16][17][18][19][20].
  • In cohorts with large proportions of SJS, lower success rates were noted, ranging from 13% to 60% [21][22][23].
  • Visual acuity improvement of 2 or more lines was noted in 40% to 100% of cohorts [13][16][17][18][19][21][23][24]

Compared to KLAL, lr-CLAL has demonstrated improved outcomes in maintain a stable ocular surface and decreased rejection [18][19][24]. In a large retrospective comparison of lr-CLAL and KLAL with a mean follow-up of 7.2 years, Cheung et. al demonstrated that 82.5% of lr-CLAL eyes maintained a stable ocular surface compared to 64.7% of KLAL eyes[6]. Lr-CLAL eyes in this study also demonstrated less failed ocular surfaces, less acute rejection episodes overall, and more resolved acute rejection episodes after treatment. Thus, in patients with total LSCD and a compatible living donor, lr-CLAL should be the first option.

Complications

Acute immunologic rejection is the most common postoperative complication. It typically presents with pain, conjunctival injection, graft swelling and engorgement, and a progressive epithelial rejection line [25][26][27]. Rates of acute rejection for lr-CLAL range from 10% to 40% in larger series of 10 or more eyes [13][14][15][16][21][22][23]. Acute rejection is treated by increasing dosage and frequency of topical and systemic corticosteroids. Subconjunctival injection of triamcinolone may also be used. Systemic immunosuppression may need to be optimized. Corticosteroids are tapered according to the decrease in ocular surface inflammation, vessel engorgement, local chemosis, and resolution of the epithelial rejection line.

Chronic rejection presents more insidiously, with gradual surface failure (progressive corneal conjunctivalization or vascularization) and graft thinning. Chronic rejection is better treated with an increase in the dosage of systemic immunosuppressive medications.

References

  1. ↑ Haagdorens, M., et al., Limbal Stem Cell Deficiency: Current Treatment Options and Emerging Therapies. Stem Cells Int, 2016. 2016: p. 9798374.
  2. ↑ 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. ↑ Kenyon, K.R., Rapoza, P.A. Limbal allograft transplantation for ocular surface disorders. Ophthalmology 1995; 102(suppl):101-102.
  4. ↑ Holland EJ. Epithelial transplantation for the management of severe ocular surface disease. Trans Am Ophthalmol Soc 1996; 94:677-743.
  5. ↑ Cheung AY, Sarnicola E, Kurji KH, et al. Cincinnati Protocol for Preoperative Screening and Donor Selection for Ocular Surface Stem Cell Transplantation. Cornea 2018;37(9):1192-1197. DOI: 10.1097/ICO.0000000000001662.
  6. ↑ 6.0 6.1 Cheung AY, Eslani M, Kurji KH, et al. Long-term Outcomes of Living-Related Conjunctival Limbal Allograft Compared With Keratolimbal Allograft in Patients With Limbal Stem Cell Deficiency. Cornea 2020;39(8):980-985. DOI: 10.1097/ICO.0000000000002329.
  7. ↑ Tsubota K, Shimmura S, Shinozaki N, Holland EJ, Shimazaki J. Clinical application of living-related conjunctival-limbal allograft. Am J Ophthalmol 2002;133:134-5.
  8. ↑ 8.0 8.1 8.2 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.
  9. ↑ Biber JM, Skeens HM, Neff KD, Holland EJ. The cincinnati procedure: technique and outcomes of combined living-related conjunctival limbal allografts and keratolimbal allografts in severe ocular surface failure. Cornea 2011;30:765-71.
  10. ↑ 10.0 10.1 10.2 Cheung AY, Sarnicola E, Kurji KH, et al. Cincinnati Protocol for Preoperative Screening and Donor Selection for Ocular Surface Stem Cell Transplantation. Cornea 2018;37:1192-7.
  11. ↑ Biber JM, Skeens HM, Neff KD, Holland EJ. The cincinnati procedure: technique and outcomes of combined living-related conjunctival limbal allografts and keratolimbal allografts in severe ocular surface failure. Cornea 2011;30:765-71.
  12. ↑ Cheung AY, Sarnicola E, Govil A, Holland EJ. Combined Conjunctival Limbal Autografts and Living-Related Conjunctival Limbal Allografts for Severe Unilateral Ocular Surface Failure. Cornea 2017;36:1570-5.
  13. ↑ 13.0 13.1 13.2 Daya SM, Ilari FA. Living related conjunctival limbal allograft for the treatment of stem cell deficiency. Ophthalmology 2001;108:126-33; discussion 33-4.
  14. ↑ 14.0 14.1 Javadi MA, Jafarinasab MR, Feizi S, Karimian F, Negahban K. Management of mustard gas-induced limbal stem cell deficiency and keratitis. Ophthalmology 2011;118:1272-81.
  15. ↑ 15.0 15.1 Scocco C, Kwitko S, Rymer S, Marinho D, Bocaccio F, Lindenmeyer R. HLA-matched living-related conjunctival limbal allograft for bilateral ocular surface disorders: long-term results. Arq Bras Oftalmol 2008;71:781-7.
  16. ↑ 16.0 16.1 16.2 Kwitko S, Marinho D, Barcaro S, et al. Allograft conjunctival transplantation for bilateral ocular surface disorders. Ophthalmology 1995;102:1020-5.
  17. ↑ 17.0 17.1 Huang T, Wang Y, Zhang H, Gao N, Hu A. Limbal allografting from living-related donors to treat partial limbal deficiency secondary to ocular chemical burns. Arch Ophthalmol 2011;129:1267-73.
  18. ↑ 18.0 18.1 18.2 Titiyal JS, Sharma N, Agarwal AK, Prakash G, Tandon R, Vajpayee R. Live Related versus Cadaveric Limbal Allograft in Limbal Stem Cell Deficiency. Ocul Immunol Inflamm 2015;23:232-9.
  19. ↑ 19.0 19.1 19.2 Eslani M, Kurji, K.; Pierson, K.; Cheung, A.Y.; Sarnicola, E.; Holland, E.J. Long-term Outcomes of Living-related Conjunctival Limbal Allograft Compared to Keratolimbal Allograft in Patients with Limbal Stem Cell Deficiency.  Cornea and Eye Banking Forum. Chicago, IL2018.
  20. ↑ Barreiro TP, Santos MS, Vieira AC, de Nadai Barros J, Hazarbassanov RM, Gomes JA. Comparative study of conjunctival limbal transplantation not associated with the use of amniotic membrane transplantation for treatment of total limbal deficiency secondary to chemical injury. Cornea 2014;33:716-20.
  21. ↑ 21.0 21.1 21.2 Gomes JA, Santos MS, Ventura AS, Donato WB, Cunha MC, Hofling-Lima AL. Amniotic membrane with living related corneal limbal/conjunctival allograft for ocular surface reconstruction in Stevens-Johnson syndrome. Arch Ophthalmol 2003;121:1369-74.
  22. ↑ 22.0 22.1 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;140:223-30.
  23. ↑ 23.0 23.1 23.2 Samson CM, Nduaguba C, Baltatzis S, Foster CS. Limbal stem cell transplantation in chronic inflammatory eye disease. Ophthalmology 2002;109:862-8.
  24. ↑ 24.0 24.1 Wylegala E, Dobrowolski D, Tarnawska D, et al. Limbal stem cells transplantation in the reconstruction of the ocular surface: 6 years experience. Eur J Ophthalmol 2008;18:886-90.
  25. ↑ Thoft RA, Sugar J. Graft failure in keratoepithelioplasty. Cornea 1993;12:362-5.
  26. ↑ Ang AY, Chan CC, Biber JM, Holland EJ. Ocular surface stem cell transplantation rejection: incidence, characteristics, and outcomes. Cornea 2013;32:229-36.
  27. ↑ Baradaran-Rafii A, Eslani M, Djalillian AR. Complications of keratolimbal allograft surgery. Cornea 2013;32:561-6.
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