Keratolimbal Allograft

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42

Keratolimbal Allograft

Background

Keratolimbal allograft (KLAL) is a technique in which allogeneic cadaveric limbal stem cells are transplanted to a recipient eye with severe ocular surface disease using peripheral donor cornea as a carrier.1 A number of techniques for KLAL have been reported, many of which describe strategies to facilitate harvesting the donor limbal grafts and donor tissue dissection. One of the earliest techniques, termed ‘keratoepithelioplasty,’ was to dissect the limbal tissue from a whole globe.2 Tsubota and co-workers reported the use of stored corneoscleral rims for limbal stem cell transplantation, which allowed for better coordination of surgery after suitable donor tissue was retrieved.3 Holland and Schwartz further modified the technique to use two stored corneoscleral rims instead of one, in order to fashion a contiguous ring of KLAL lenticules around the recipient limbus, which doubled the quantity of limbal stem cell supply and created a barrier to conjunctivalization.4 Djajilian reported a conjunctival-based thin KLAL technique which employed fibrin glue alone to secure the limbal allografts using minimal or no peripheral scleral skirt.5

Optical keratoplasty, either deep anterior lamellar keratoplasty (DALK) or penetrating keratoplasty (PK), may be required after KLAL, if deeper corneal stromal scarring is present. Sundmacher et al. have described a procedure termed homologous penetrating central limbokeratoplasty, in which a stored corneoscleral rim is intentionally trephined off-center to create a penetrating keratoplasty button.6 Using this technique, approximately 30–40% of the graft circumference contains limbal stem cells, and the patient benefits from receiving a clear penetrating graft along with limbal stem cells in a single operation. However, in severe cases of LSCD, it may be more beneficial to have limbal stem cells through 360 degrees. Performing optical keratoplasty as a staged procedure at least 3–6 months after KLAL allows for decreased ocular surface inflammation and stabilization of the corneal epithelium.

Indications

Keratolimbal allograft surgery is performed in patients who have no suitable living-related donor and have either bilateral LSCD or unilateral LSCD and fear damage to the healthy fellow eye (Fig. 42.1). Patients need to be suitable candidates for systemic immunosuppression, which is crucial to the success of KLAL in stabilizing the ocular surface and restoring a normal corneal epithelium phenotype.7–9

KLAL is ideal for diseases, such as aniridia, contact lens wear-related LSCD, and iatrogenic LSCD that affect mainly the limbus with minimal to no involvement of the conjunctiva.1,7,10 Patients with total LSCD require 360-degree KLAL, while those with sectoral LSCD may require only sectoral KLAL.

In patients with mild chemical injuries, Stevens – Johnson syndrome (SJS) or ocular cicatricial pemphigoid (OCP) and who have LSCD with mild to moderate conjunctival inflammation, it is best if the eye is allowed to quiet for at least a year or more prior to KLAL surgery in order to increase the chances of graft survival. The success rate of KLAL decreases with increasing conjunctival inflammation, such as in severe cases of chemical injuries, SJS, or OCP.1 In these cases, there is chronic conjunctival inflammation and scarring, decreased mucin and aqueous tear deficiency, and great potential for keratinization of the ocular surface. Since KLAL alone does not provide any healthy conjunctiva, for these severe cases of ocular surface disease, one can use in conjunction with two KLAL segments from one donor corneoscleral rim, living-related conjunctival limbal allograft (lr-CLAL) for bilateral disease and conjunctival limbal autograft (CLAU) for unilateral disease (Fig. 42.2).11,12

Preoperative Considerations

Prior to any limbal stem cell transplantation procedure, including KLAL, it is crucial that any lid functional abnormalities, exposure, and severe aqueous tear deficiency, be addressed. Eyelid abnormalities, such as lagophthalmos, misdirected lashes, malpositioned or keratinized lid margins, should be operated on prior to KLAL. The prognosis for KLAL is poor in patients with an abnormal or absent blink reflex, as persistent epithelial defects may develop with risk of scarring and infection. Patients with severe aqueous tear deficiency lack essential tear components and may benefit from autologous serum drops used regularly after KLAL.

Patients, such as those after chemical injury, who have glaucoma or uncontrolled intraocular pressure, should undergo glaucoma drainage device implantation prior to KLAL, since multiple glaucoma medications may contribute to additional ocular surface toxicity (Fig. 42.3). Long-term use of topical corticosteroids to prevent graft rejection will also further aggravate any pre-existing glaucoma.

KLAL is contraindicated in patients with significant keratinization of the ocular surface.1 Uncontrolled severe inflammation is another poor prognostic factor for KLAL. Amniotic membrane grafts may be used in conjunction with KLAL to suppress inflammation and facilitate epithelialization.9 Finally, systemic immunosuppression medications plays an important role and patient compliance must be assured prior to KLAL, since noncompliance has been shown to be the main reason for graft rejection and failure.13

Donor Tissue Considerations

Tissue Selection

Donor tissue supplied by an eye bank and stored in Optisol™ has greatly facilitated the ease of planning for KLAL procedures. However, the surgeon must communicate with the eye bank regarding availability of tissue and educate the staff regarding the special tissue requirements for KLAL. In contrast to the standard emphasis on preserving corneal endothelium and stroma for penetrating keratoplasty (PK) and endothelial keratoplasty (EK), for tissue to be used in KLAL, the donor limbal epithelium needs to be protected from any trauma. ‘Excellent epithelium’ is an important specification and if the corneal epithelial layer appears entirely normal, the surgeon may be reassured that the limbal stem cells have undergone minimal harm during procurement.

Based on the authors’ experience with supply of KLAL tissue from the Minnesota Lions Eye Bank, in addition to the Eye Bank Association of America guidelines, the following donor tissue selection guidelines have provided high-quality donor KLAL tissue:

Eye Bank Tissue Preparation

Another difference from tissue preparation for PK or EK is that a 3–4-mm skirt of peripheral conjunctiva along with a 4–5-mm scleral rim is left on the corneoscleral rim for KLAL transplantation (Fig. 42.4). Leaving both this conjunctival and scleral rim minimizes damage to the limbal area and provides some goblet cells which are often deficient in recipient eyes. There has been no evidence to indicate any increased risk of infection by leaving the conjunctival rim intact.

For 360-degree limbal coverage using KLAL tissue, the corneoscleral rims from both eyes of the same donor are used for one recipient eye. In cases in which KLAL is performed in conjunction with living-related conjunctival limbal allograft (‘Cincinnati procedure’) or conjunctival limbal autograft (‘Modified Cincinnati procedure’) surgery, only one corneoscleral rim is needed.11,12

Surgical Technique

Preparation of the Donor Tissue

The central cornea of each corneoscleral rim is excised with a 7.5-mm trephine as in routine keratoplasty. Under a surgical microscope, the rim is then sectioned into two halves and trimmed to leave approximately 2–3 mm of sclera peripheral to the limbus. The posterior sclera and corneal stroma, including Descemet’s membrane and endothelium of each segment are removed by lamellar dissection using a sharp rounded crescent blade and curved Vannas scissors. The prepared KLAL lenticules are then placed in storage media solution.

If the surgeon does not have an assistant to provide countertraction during tissue preparation, he or she may utilize cyanoacrylate glue to stabilize the KLAL scleral bed onto a sterile plastic platform followed by a thin strip of viscoelastic near the anterior edge of the lenticule during donor dissection of the anterior corneal stroma and donor conjunctival limbal tissue.5

Preparation of the Recipient Eye

A 360° conjunctival peritomy is performed, including release of any symblephara that are present at the limbus. The conjunctiva is allowed to recess 2–3 mm from the limbus. This often occurs naturally due to previous tension from scarring. Tenon’s capsule is often extremely thick in these eyes due to chronic inflammation and may be liberally excised with care taken to preserve the overlying conjunctiva. In the rare event that excess conjunctiva is present, a conservative amount may be trimmed. Topical epinephrine (1 : 10 000 dilution) and wet-field cautery are used to control for hemostasis and to allow for better visualization of the surgical field. Abnormal corneal epithelium and fibrovascular pannus are then removed by superficial keratectomy using a No. 64 Beaver or equivalent crescent blade, taking care to avoid cutting deep into stroma.

Placement of the Donor Tissue

Each KLAL segment may be secured at the limbal edge using two 10-0 nylon sutures cut very short. The segments may then be trimmed as needed so that they do not overlap. Fibrin tissue glue is applied to secure the base of the KLAL lenticules to the recipient sclera and to ensure that the conjunctiva sits abutting the posterior edge of the KLAL lenticule. During suturing, the KLAL tissue should be protected from trauma with a viscoelastic coating. If the donor tissue is very thin, fibrin glue alone may be used to secure the lenticules (Fig. 42.5).

It is crucial to place the three donor segments immediately adjacent to one another to avoid any gaps between tissues, which could allow conjunctival invasion onto the surface. The authors recommend that the host and donor conjunctiva be well approximated to each other or to have the host conjunctiva slightly pulled over the donor conjunctiva. This avoids the possibility of host conjunctival growth under the grafts while also preventing the formation of inclusion cysts.

Postoperative Care

Local Management and Systemic Immunosuppression

At the conclusion of the KLAL procedure, subconjunctival corticosteroids and cefazolin are injected into the recipient eye. A 16.0 or 18.0-mm (9.8-mm base curve) soft bandage contact lens (BCL) (Kontur Contact Lens, Co, Richmond, CA) is placed, and a protective patch and shield is taped on for 4 hours. At home, the patient removes the patch and shield and begins the standard topical medications used after routine PK: topical cyclosporine 0.05% twice daily (for the duration of the patient’s follow-up), difluprednate (or prednisolone acetate 1%) four times daily (for the first 3 months then tapered by 1 drop per month according to the degree of ocular surface inflammation), a fourth-generation fluoroquinolone four times daily (until the corneal epithelium is healed and at which time the BCL is also removed), and frequent non-preserved artificial tears.

Systemic immunosuppression must be used in patients after KLAL to prevent immune rejection of the allograft tissue and to manage the chronic inflammation present in eyes with severe ocular surface disease. Inflammation may lead to destruction of transplanted stem cells in the short and long term. A regimen consisting ideally of systemic steroids, tacrolimus, and mycophenolate mofetil has been used with good success to increase graft survival.5,8,9 Triple treatment consisting of systemic steroids, cyclosporine, and azathioprine has previously been used. Co-management with an organ transplant specialist with experience in the use of these immunosuppression medications is highly recommended.

Optical Keratoplasty

After achieving a stable ocular surface with KLAL (see Fig. 42.3Bb), subsequent optical keratoplasty may be performed to clear any deep stromal scarring (see Fig. 42.3C). It is advisable to wait at least 3–6 months to achieve a stable ocular surface before proceeding with PK or DALK. There are technical challenges in corneal transplantation after ocular surface stem cell transplantation. Usually, larger-diameter trephinations (approximately 9.5 to 11 mm) are sized to abut the border of the KLAL tissue. Donor buttons should be oversized by 0.5 mm, since eyes with chronic inflammation or cicatricial disease from chemical injury often contract after trephination of the host cornea. Deep bites should be employed with 24 interrupted 10-0 nylon sutures to ensure that the donor and host cornea are fully approximated, avoiding suturing just to the superficial KLAL segment.14

Outcomes

Graft survival rates for KLAL range from 33% to 84%.15 The use of systemic immunosuppression after KLAL is required to decrease the risk of graft failure secondary to rejection. This subject is discussed more extensively in Chapter 46.

The best results after limbal stem cell transplantation are achieved with adequate triple systemic immunosuppression. In a study of 31 eyes of 23 patients with aniridia after KLAL with follow-up of 12 to 117 months, 23 eyes (74.2%) achieved a stable ocular surface, and overall mean visual acuity improved from 20/1000 to 20/165.7 A study of 19 eyes from 16 patients demonstrated a KLAL survival rate of 76.9% after a follow-up of 31 months.5 Fifteen eyes (78.9%) showed an improvement in vision of two or more Snellen lines. Another study of 12 eyes from 10 patients with follow up of 36 to 91 months after KLAL reports a stable ocular surface achieved in 83%.9

In evaluating the success of KLAL, it is also important to consider the length of follow-up. Three to four months after PK, a healthy-appearing ocular surface may be populated by the transplanted adult epithelial cells of the donor cornea only. It can be a year or more before the limbal stem cells are called upon to repopulate the ocular surface. Hence, more than 1 year of follow-up after KLAL is needed to pass judgment on the procedure’s success.

References

1. Holland, EJ. Epithelial transplantation for the management of severe ocular surface disease. Trans Am Ophthalmol Soc. 1996;94:677–743.

2. Thoft, RA. Keratoepithelioplasty. Am J Ophthalmol. 1984;97:1–6.

3. Tsubota, K, Toda, I, Saito, H, et al. Reconstruction of the corneal epithelium by limbal allograft transplantation for severe ocular surface disorders. Ophthalmology. 1995;102:1486–1496.

4. 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.

5. Nassiri, N, Pandya, HK, Djalilian, AR. Limbal allograft transplantation using fibrin glue. Arch Ophthalmol. 2011;129:218–222.

6. Reinhard, T, Sundmacher, R, Spelsberg, H, et al. Homologous penetrating central limbo-keratoplasty (HPCLK) in bilateral limbal stem cell insufficiency. Acta Ophthalmol Scand. 1999;7:663–667.

7. Holland, EJ, Djalilian, AR, Schwartz, G. Management of aniridic keratopathy with keratolimbal allograft: a limbal stem cell transplantation technique. Ophthalmology. 2003;110:125–130.

8. 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. 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.

10. Schwartz, GS, Holland, EJ. Iatrogenic limbal stem cell deficiency. Cornea. 1998;17:31–37.

11. 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.

12. 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;31:655–661.

13. Andrea, AY, Chan, CC, Biber, JM, et al. Ocular surface stem cell transplantation rejection: incidence, characteristics, and outcomes. Cornea. 2012. [June 4].

14. Biber, JM, Neff, KD, Holland, EJ, et al, Corneal transplantation in ocular surface disease. Cornea, 3rd ed. Krachmer, JH, Mannis, MJ, Holland, EJ, eds. Cornea, vol. 2. Elsevier: London, 2010:1755–1758.

15. Cauchi, PA, Ang, GS, Azuara-Bianco, A, et al. A systematic literature review of surgical interventions for limbal stem cell deficiency in humans. Am J Ophthalmol. 2008;146:251–259.

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