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have not only the worst natural disease course but also the length of follow-up, and postoperative Snellen best spectacle–
poorest prognosis for surgical rehabilitation.2 Patients in- corrected visual acuity.
cluded in this study were primarily defined as either stage IIc The stability of the ocular surface was determined by
or IIb. slit-lamp examination performed by one examiner (E.J.H.) and
Keratolimbal allograft (KLAL) surgery is used to treat the presence or absence of late staining with fluorescein dye.
LSCD, which targets the specific cell of dysfunction—the limbal The ocular surface was defined as stable, improved, or failed.
stem cell. In a KLAL procedure, stem cells are obtained from A stable ocular surface had an intact corneal epithelium
a cadaveric donor and transplanted to the recipient host limbus. In without any conjunctivalization of the surface or inflamma-
the patients with combined limbal stem cell injury and severe tion. An improved ocular surface was defined as an eye with
conjunctival inflammation, healthy conjunctiva needs to be partial failure with areas of healthy corneal and areas of
transplanted along with the stem cells. KLAL does not involve abnormal conjunctival epithelium on the cornea. Eyes labeled
the transplantation of healthy conjunctiva onto the ocular surface. as improved ocular surface did not have any inflammation and
Studies have concluded that conjunctival epithelium is derived were deemed appropriate for the implantation of a keratopros-
from a stem cell population that is separate from the limbus.3 thesis. The lr-CLAL/KLAL improved these patients by
Therefore, KLAL alone is not sufficient to correct eyes with stabilizing the ocular surface, improving the tear film, adding
diffuse surface failure caused by concomitant loss of both the goblet cells and mucin production to the surface, providing
epithelial stem cell populations. A living-related conjunctival barriers to symblepharon formation, and creating better
limbal allograft (lr-CLAL) allows for the transplantation of fornices to allow for a better contact lens fitting if keratopros-
healthy conjunctiva and limbal stem cells from a patient’s living thesis was required. A failed ocular surface described an eye
and related donor. This is more beneficial than KLAL alone in with recurrence of total LSCD.
this severely inflamed population of patients. Other advantages of Preoperatively, a living-related donor was chosen based
lr-CLAL include a lower antigenic challenge because of on the best histocompatibility match of living-related donors
histocompatibility matching and the replacement of goblet cells volunteering for the procedure. If only 1 family member
to increase mucin production and better stabilize the recon- offered donation, this tissue was used. A full ophthalmic exami-
structed ocular surface. The primary disadvantage of lr-CLAL nation was performed on this individual. All surgeries were
alone is transplantation of a small number of stem cells that only performed at the Cincinnati Eye Institute by a single surgeon
cover about 50% of the limbus, leaving the other 50% without a (E.J.H.). The following technique was used for all the cases.
barrier for possible invasion and spread of conjunctival
inflammation. Harvesting the Living-Related Donor Tissue
We have developed the ‘‘Cincinnati procedure,’’ which The previously described technique of obtaining the
combines an lr-CLAL and a KLAL. Previous reports in conjunctival graft from the living-related donor in the 12- and
the literature have not reported on the success rate of the 6-o’clock meridians was used.4 Briefly, the nondominant
Cincinnati procedure. This article reports the surgical eye of the living-related donor was addressed first in the
technique and outcomes of 24 cases of recipients undergoing 12-o’clock meridian. A gentian violet surgical marking pen
lr-CLAL/KLAL for severe combined limbal stem cell and was used to mark the conjunctival portions of the grafts. The
conjunctival deficiency. This article will also discuss the conjunctiva was elevated from the Tenon layer with balanced
utilization and success of keratoplasty and systemic immu- salt solution on a tuberculin syringe. Dissection of the graft
nosuppression (IS) in this challenging population. began by incising with Westcott scissors along the lateral
borders. The tissue was undermined using a blunt Westcott
scissor. The posterior border of the graft was cut. The
PATIENTS AND METHODS conjunctiva was reflected anteriorly over the cornea, and blunt
A retrospective chart review of 19 patients undergoing dissection was continued anteriorly into the peripheral corneal
the ‘‘Cincinnati procedure’’ between 1999 and 2009 was per- vascular arcades to ensure inclusion of the stem cells. Once the
formed. All patients were included who underwent combined tissue was free, it was transferred to balanced salt solution, and
lr-CLAL/KLAL and had follow-up greater than 1 year. the same procedure was performed in the 6-o’clock meridian.
Parameters obtained included age, sex, indication for surgery, After retrieval of both meridians of the tissue, the conjunctival
preoperative Snellen best spectacle–corrected visual acuity, defect was closed with two 7-0 vicryl sutures, 1 mm posterior
intraoperative complications, postoperative complications, to the limbus.
Preparation of the Cadaveric Donor Tissue 9-o’clock meridians also in the same anatomical orientation
The preparation of the cadaveric donor tissue for stem with the limbal edge at the recipient limbus. A 10-0 nylon
cell transplantation has been described.5 It is important to suture was used, and the knots were not buried (Figures 1–4).
request donor tissue from the eye bank that includes a 3- to 4-
mm conjunctival and scleral rim for the limbal stem cell Postoperative Medications
transplantation.6 The central cornea of the corneoscleral rim Postoperative topical management of stem cell trans-
was excised with a 7.5-mm trephine on an Iowa press. The plantation is consistent with the topical management of
remaining corneoscleral rim was cut into equal halves, and postoperative penetrating keratoplasty (PK) in our facility.
scissors were used to dissect the excess peripheral scleral tissue. Four hours after the completion of the procedure, recipients
The posterior one half to two thirds of each hemisection was begin a topical cyclosporine 0.05% 2 times daily, along with
removed by lamellar dissection using a crescent blade. The topical prednisolone acetate 1% 4 times daily, and a topical
2 pieces were placed in Optisol (Chiron Ophthalmics, Irvine, fourth-generation fluoroquinolone 4 times daily. Oral immu-
CA) until placed on the eye later in the operation. nosuppressive medications are administered as determined
preoperatively by the University of Cincinnati Renal Trans-
Preparation of the Recipient Eye plant Team. Our current IS regimen consists of tacrolimus,
The preparation of the recipient eye has also been mycophenolate mofetil, and a short course of oral prednisone
described.5 Briefly, a 360-degree limbal peritomy was per- (3 months or less). Tacrolimus dosing is adjusted based on
formed. Any areas of symblepharon were lysed at the limbus, levels taken on a monthly basis and is typically tapered off at
and the conjunctival tissue was undermined and allowed to 12 to 18 months. Most patients are maintained on mycophe-
retract posteriorly 2 to 3 mm from the limbus with Westcott nolate mofetil as monotherapy for at least 24 to 36 months
scissors. Light wet-field cautery and topical epinephrine depending on the level of inflammation and tolerance to
(1:10,000 dilution) was used to maintain hemostasis. Excess medicine. Topical prednisolone was maintained at 4 times daily
Tenon tissue was excised with Westcott scissors. Any for the first 3 months and then decreased by 1 drop per month
abnormal corneal epithelium and fibrovascular pannus were until an appropriate maintenance dose was achieved. Topical
removed by superficial dissection with a number 64 Beaver cyclosporine was continued twice daily throughout the follow-
or crescent blade (Fig. 1). up period, and the topical fluoroquinolone was discontinued
after the epithelium was healed.
Placement of Donor Tissue
The harvested living-related tissue was sutured in Keratoplasty Techniques
the same anatomical orientation with the limbal edge at the In a patient who has undergone previous stem cell
recipient limbus in the 12- and 6-o’clock meridians first. transplantation, keratoplasty is often more technically chal-
The tissue was sutured with 10-0 nylon, and the knots were lenging. We advocate making some minor adjustments to the
not buried to prevent trauma and cheese wiring of the donor technique to ensure long-term success. First, large-diameter
tissue. The cadaveric donor segments were placed at the 3- and PK is necessary to allow for optimal wound healing. We size
keratoplasty. 57.9% (11 of 19) patients underwent repeat these abnormal levels returned to normal with modifications in
keratoplasty with 5 PK and 6 KPro (Fig. 5). the medication regimen.
Visual Outcomes
Preoperative best-corrected visual acuity was 20/400 or DISCUSSION
worse in 87.5% (21 of 24) of eyes; 75% (18 of 24) of eyes had Successful treatment of the patients with ocular surface
an improvement in vision of at least 1 line at the last follow-up; disease requires the clinician to aggressively treat not only the
16.6% (4 of 24) eyes had the same postoperative visual acuity underlying condition but also all the comorbidities that can
as those estimated preoperatively. Two eyes (8.3%) had affect the patients’ visual outcome. Patients with ocular surface
a decrease in vision from their preoperative vision. One patient failure often have a combination of 2 or more of the following:
lost vision because of end stage glaucoma, and the other LSCD, conjunctival deficiency, severe dry eye, corneal
required enucleation after perforation; 70.8% of patients (17 of scarring and melting, glaucoma, cataract, or lid abnormalities.
24) achieved 20/125 vision or better at the last follow-up. Conjunctival deficiency is defined as an extensive conjunctival
37.5% (9 of 24) of patients achieved 20/50 vision or better inflammation, which can result in symblepharon formation
postoperatively at the last follow-up visit (Fig. 6). Of patients and extensive goblet cell loss with mucin deficiency. The end
with a KPro, 90.0% (9 of 10) had an improvement in vision result of conjunctival deficiency is the keratinization of the
with 70.0% achieving 20/125 vision or better at the last ocular surface including the conjunctiva and cornea. Stem cell
follow-up. transplantation is difficult in patients with stage IIb or IIc
disease because of the severe dry eye as a result of aqueous and
IS Exposure and Adverse Events mucin deficiency, active inflammation, abundance of immune
95.8% (23 of 24) of patients received systemic IS. Mean mediators present, and conjunctival scarring with symble-
time on IS was 34.1 months (range: 7.6 to 99.7 months). 17.4% pharon. For these reasons, these patients have not only the
(4 of 23) of patients were able to be successfully tapered off IS. worst natural disease course but also the poorest prognosis for
Mean time to tapering of IS was 43.2 months (range: 18.0 to surgical rehabilitation.2 Transplantation of the limbal stem
89.1 months). Systemic side effects of IS include severe cells only, such as in KLAL, addresses only one of the factors
adverse events such as death, myocardial infarction, cerebro- that contribute to their ocular surface failure. Therefore, we
vascular event, and secondary tumors, and minor adverse proposed combining conjunctival limbal allograft and KLAL
events of IS include alterations in biochemistry, increase in as a procedure in patients with both limbal and conjunctival
cardiovascular risk factors, and infections requiring hospital- deficiency.
izations. We report 0 severe adverse events and 6 (26.1%) The transplantation of the conjunctiva and stem cells
minor adverse events. Of the minor adverse events, 4 patients provides the additional benefit of goblet cells from the
had a temporary increase in the blood creatinine level, and 2 additional conjunctiva, which makes this procedure useful in
patients had a transient increase in liver function tests. All the management of eyes with cicatrizing conjunctival disease
such as SJS, OCP, and some chemical injuries. However, this vascularized nature of the recipient’s cornea before trans-
procedure is not successful in patients who have progressed to plantation, often increasing the risks of rejection. Oral and
diffuse keratinization of the ocular surface. A disadvantage of topical IS does lower this risk; however, other important
lr-CLAL alone compared with KLAL is that the amount of advantages of lamellar keratoplasty include reduction of
limbus that can be harvested from the donor eye is limited, intraocular complications, such as expulsive hemorrhage,
resulting in significantly fewer stem cells with lr-CLAL glaucoma, cataract, and endophthalmitis.8 One major disad-
compared with KLAL. With regard to tissue utilization, the vantage of lamellar keratoplasty in this setting is the inability
combined procedure uses only 1 corneoscleral rim, which is to assess the health of the endothelium because of anterior
divided into 2 KLAL segments, as opposed to 2 donor eyes for stromal scarring.9
KLAL. Another potential disadvantage of this procedure Historically, the Boston type I or II KPro has been
compared with KLAL alone is the risks to the donor and the reserved for patients without a stable ocular surface, a history of
time required to identify and test the donor and increased multiple failed grafts, or those unable to tolerate surface
operative time. In this series, we did not have any adverse reconstruction and IS. The type II KPro is designed to be
events to the donor such as LSCD, persistent epithelial defects, inserted through the lid in patients with a severely dry ocular
infection, or loss of vision. surface and no fornices to support the keratoprosthesis.
In this population, corneal scarring was often visually Complications of the type II KPro include endophthalmitis,
limiting and did not improve to a satisfactory level after skin retraction, retroprosthetic membrane, worsening of
surface reconstruction. To achieve better vision, 79.2% of the glaucoma, and tissue melting.10 We did not implant any
eyes in this study required keratoplasty. We advocate a staged patients with a type II KPro. Implantation of a type I KPro in
approach to decrease the amount of inflammation in hopes patients with severe ocular surface disease (stage IIb or IIc) and
of providing the optimal recipient bed for the keratoplasty conjunctival deficiency is challenging for multiple reasons.
success. At 3 months postoperatively, the ocular surface is Symblepharon and shortened fornices make maintaining
evaluated and determined to be stable, improved, or failed. a bandage contact lens difficult, which can increase the risk
Patients with a failed ocular surface were offered repeat or of corneal melting and infectious keratitis.11 Sayegh et al
sectoral KLAL or KPro. If keratoplasty is indicated, it is reported on the outcomes and complication of 16 eyes of
typically recommended to patients with either stable or patients with SJS that underwent implantation of either type I or
improved ocular surfaces. As for type of keratoplasty, we type II Boston KPro; 25% of these patients developed tissue
commonly advocate 3 types of transplants: PK, deep anterior melting and aqueous leakage that required surgical manage-
lamellar keratoplasty, or Boston type I KPro (Fig. 7) The ment.10 Based on this study, tissue melting and leaking are
health of the endothelial layer is vital to decide between higher in patients with SJS compared with the overall incidence
penetrating and lamellar keratoplasty. In cases of abnormal of corneal melting (17%) with Boston KPro for all indications.12
endothelium, we use PK. Lamellar keratoplasty has the We believe that the Boston type I KPro can be used as
primary advantage of avoiding the unnecessary replacement the primary keratoplasty in patients who have undergone
of healthy endothelium, thus obviating the problems of ocular surface reconstruction and have a stable or improved
endothelial rejection and hence subsequent endothelial graft surface as well. Combined lr-CLAL/KLAL before implanta-
failure.8 We believe that this is even more significant in this tion of a KPro is beneficial because it improves the ocular
population because of the highly inflamed and often surface and tear film, which we believe would lower the
incidence of melting and possible extrusion of the implant. keratoprosthesis without stem cell transplantation in patients
In addition, the limbal stem cell grafts provide barriers for with severe stage IIb or IIc ocular surface disease.
recurrent symblepharon formation and help to create and
maintain the fornix. This structural function enhances the REFERENCES
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patients with a KPro had an improvement in vision with 70.0% belong to two separate lineages. Invest Ophthalmol Vis Sci. 1996;37:523–533.
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