Abstract
Objective
To evaluate the surgical results and the variables affecting the outcomes in conjunctival-limbal allograft transplantation (CLAL).
Methods
Patients who underwent CLAL for limbal stem cell deficiency (LSCD) between 2007 and 2019 were included in the study. LSCD staging was performed according to the staging system developed by the ‘Limbal Stem Cell Working Group’. Stage 1C and higher stage LSCD patients were included in the study. ‘Successful surgical outcome’ was defined as improvement in LSCD stage at 1 year postoperatively.
Results
A total of 19 eyes of 19 LSCD patients were included. The mean age of the patients was 40.21 ± 14.65 (6–65) years, and the male/female ratio was 12/7. CLAL was performed in 9 (47.3%) patients with Stage 2B, 9 (47.3%) patients with Stage 3 and 1 (5.4%) with Stage 1C. LSCD aetiology; chemical injury (12), vernal keratoconjunctivitis (2), aniridia (1), corneal degeneration (1), and unknown (3). Surgery was successful in 52.6% of cases. Surgical success was associated with lower LSCD stage (p = 0.04). Lower grades of chemical injury at presentation and a longer time interval between injury and CLAL were associated with higher surgical success (p = 0.001; p = 0.001). The mean postoperative follow-up time was 50.77 ± 29.46 (6–98) months.
Conclusions
Despite graft rejection and long-term use of immunosuppressants, CLAL is still one of the most preferred techniques in the treatment of bilateral LSCD. Preoperative LSCD stage and degree of chemical burn are important factors affecting the surgical outcome. Also, CLAL surgery should not be rushed and should be performed when inflammation has subsided.
Subject terms: Corneal diseases, Eye diseases
Introduction
Corneal epithelial stem cells, which are localised at the limbal region, are responsible for regeneration of the corneal epithelium [1–3]. Destruction of the limbus causes loss of limbal epithelial stem cells and results in limbal stem cell deficiency (LSCD) [4]. Corneal conjunctivalization and vascularisation, which may lead severe visual loss, are usually present in this condition. The leading symptoms of the disease consist of pain and photophobia along with visual loss [4].
The main treatment option for LSCD is limbal stem cell transplantation [5, 6]. In unilateral cases, successful reconstruction can be achieved by transplanting autologous limbal epithelial stem cells from the opposite eye in a procedure called a ‘conjunctival-limbal autograft’ [7, 8]. However, bilateral cases require an allogeneic source of limbal epithelial stem cells. In addition, conjunctival-limbal autograft procedure cannot be performed in unilateral cases with no evident stem cell reserve in the healthy eye. Allogeneic limbal epithelial stem cells can be obtained from living related donors by conjunctival-limbal allograft (CLAL) as well as obtained from cadaveric donors by kerato-limbal allograft (KLAL) [9–11]. CLAL has a superior surgical success because of the higher tissue combability when compared with KLAL [10].
There is limited data in the literature on transplant survival rates after CLAL. Although systemic immunosuppression is a major factor influencing CLAL outcomes, other potential factors are still undetermined [12]. In the current study, it was aimed to determine variables that effect the surgical outcome in CLAL.
Materials and methods
The medical records of LSCD patients who underwent CLAL surgery between years 2007 and 2019 were retrospectively reviewed. The patients’ medical records such as age, gender, donor-recipient biological relationship, primary aetiological cause and concomitant ocular injuries (corneal perforation, symblepharon, etc.) were evaluated. In patients with ocular chemical burn, nature of the chemical agent, time interval between injury and CLAL were also recorded. Dua Classification [13] was used for chemical injury grading. LSCD grading was performed according to the staging system developed by Deng et al. in 2019 by the ‘Limbal Stem Cell Working Group’ [14]. This grading system is mainly based on the degree of corneal involvement as follows: Stage 1- clear cornea at central 5 mm; Stage 2- central 5 mm corneal involvement; Stage 3- involvement of the entire corneal surface. Stages 1 and 2 are further graded as A, B, and C based on the degree of limbal involvement. A represents 50% limbal involvement, B more than 50% but less than 100% limbal involvement, and C 100% limbal involvement. The medical records of patients who underwent CLAL with Stage 1C and/or higher LSCD were included to this study. “Successful surgical outcome” was defined as improvement in the post-operative 1st year LSCD stage, regardless of improvement in visual acuity.
The donor limbal tissues were obtained from the healthy living relatives without performing human leucocyte antigen (HLA) tissue compatibility analysis between the recipient and the donor. All donors were serologically analysed prior to surgery.
Post-operative treatment protocol for the recipient eye was topical 0.5% moxifloxacin (Vigamox, Alcon, US), 1% loteprednol etabonate (Lotemax, Bausch and Lomb, US), cyclosporine A 1% (Restasis, Allergan, US) and preservative-free artificial tears. All patients received systemic immunosuppressive therapy for at least one year in accordance with the literature. Immunosuppressive agent selection was made according to the patient’s risk factors and health insurance status. The donor eye was treated with topical 0.5% moxifloxacin for a week.
Patients with a follow-up period of less than 6 months, a history of previous ocular surgery or trauma, and absence of anterior segment photographs or regular medical records were excluded from the study.
This retrospective study was carried out in accordance with the principles of the Declaration of Helsinki, with the approval of the Ege University Ethics Committee. Written informed consent was obtained from all participants.
Data analysis was conducted with SPSS 23.0 (Statistical Package for Social Science) package programme. In the evaluation of the data, mean, standard deviation, Friedman test for comparison of k related groups, Wilcoxon test for comparison of two related groups and multiple comparisons and chi-square test of independence were used.
Results
Conjunctival-limbal allograft transplantation was performed in 19 eyes of 19 patients with LSCD. The mean age of the patients was 40.21 ± 14.65 (6–65) with a male/female ratio of 12/7. CLAL was performed in 9 (47.3%) patients with Stage 2B, 9 (47.3%) patients with Stage 3 and 1 (5.4%) patient with Stage 1C.
The aetiological causes of the LSCD consisted of chemical injury (12 cases), vernal keratoconjunctivitis (2 cases), aniridia (1 case), corneal degeneration (1 case), and unknown (3 cases). The causative agent for chemical injury was alkaline in 5 patients (42%) and acid in 4 patients (33%). Remaining 3 (25%) chemical injury patients were exposed to undefined chemicals. According to the Dua classification, the chemical burn degrees of these 12 patients were as follows: Grade 4 in 2 (16.7%) patients, Grade 5 in 4 (33.3%) patients and Grade 6 in 6 (50%) patients.
Improvement in LSCD stage in the post-operative 1st year was considered as a ‘successful surgical outcome’. Successful surgical outcome was achieved in 10 (52.6%) patients. LSCD stage remained the same in eight patients and worsened in one patient. Surgical success was associated with lower pre-operative LSCD stage and better pre-operative BCVA (p = 0.04; p = 0.017). The donor-recipient biological relationship (first-degree or second-degree relatives) and primary aetiology did not have significant effect on surgical success rates (p = 0.35; p = 0.08).
Surgical success was achieved in five patients (41.7%) with ocular chemical burns in the postoperative 1st year. In contrast, at 1 year, LSCD stage did not change in six patients (50%) and LSCD stage worsened in one (8.3%) patient. In patients with ocular chemical burn, the degree of the chemical burn showed negative correlation with surgical success, and the results were statically significant (p = 0.001). The causative chemical agent did not have significant effect on the surgical success rates (p = 0.06). The mean time between chemical injury and CLAL surgery was 14.5 ± 10.6 (2.4–32.5) months. In chemical burn, the longer time between injury and surgery was found to be associated with the higher surgical success (p = 0.001) (Table 1) (Fig. 1).
Table 1.
Variables for CLAL Success at Post-operative First Year.
| Variables | Number of the eyes (n (%)) | p value |
|---|---|---|
| Total | 19 (100%) | |
| Surgical success at the post-operative 1st year (n (%)) | 10 (52.6%) | |
| Primary aetiology (n (%)) | 0.08 | |
| Chemical injury | 12 (63.15%) | |
| Vernal keratoconjunctivitis | 2 (10.5%) | |
| Aniridia | 1 (5.3%) | |
| Corneal degeneration | 1 (5.3%) | |
| Unknown | 3 (15.8%) | |
| Preoperative LSCD stages (n (%)) | 0.04* | |
| Stage 1C | 1 (5.4%) | |
| Stage 2B | 9 (47.3%) | |
| Stage 3 | 9 (47.3%) | |
| Chemical agent (n (%)) | 0.06 | |
| Alkaline | 5 (42%) | |
| Acid | 4 (33%) | |
| Other/mixed | 3 (25%) | |
| Dua chemical injury grade (n (%)) | 0.001* | |
| Grade 4 | 2 (16.7%) | |
| Grade 5 | 4 (33.3%) | |
| Grade 6 | 6 (50%) | |
| Time interval between chemical injury and surgery (months) | 0.001* | |
| Mean ± SD (Range) | 14.5 ± 10.6 (2.4–32.5) |
CLAL conjunctival-limbal allograft, LSCD limbal stem cell deficiency.
*p < 0.05 was considered significant.
Statistically significant p-values are in bold.
Fig. 1. The relationship between time to surgery after chemical injury and surgical success.
When the successful and unsuccessful groups are examined in terms of time to allograft surgery, it can be said that the time to surgery is longer on average in patients who have had successful surgery compared to those who have failed.
Symblepharon was the most common pre-operative concomitant disease, accounting for seven cases. In addition, one patient had corneal perforation. The remaining 11 cases did not have any concomitant diseases at the time of presentation. Thirteen of the patients were undergone other surgical interventions simultaneously with CLAL surgery. These were symblepharon release (seven patients), amniotic membrane transplantation (four patients) and penetrating keratoplasty (two patients). The mean post-operative follow-up time was 50.77 ± 29.46 (6–98) months.
Although BCVA is not essential in the evaluation of surgical success according to the new LSCD staging system, the mean pre-operative BCVA significantly improved following the surgery. The mean preoperative BCVA was 1.43 ± 0.92 (0.5–3.1) logMAR and the mean final BCVA at post-operative 1st year was 0.87 ± 0.94 (0–3.1) logMAR; the difference was statistically significant (p = 0.014).
Following CLAL, 13 patients underwent further surgical procedures including penetrating keratoplasty (5), trabeculectomy (2), amniotic membrane transplantation (1), seton tube implantation (1), punctum plug (1), and phacoemulsification (3).
The mean time between CLAL and keratoplasty was 21.78 ± 22.58 (4.8–60) months. In all patients with additional keratoplasty, BCVA improved (Fig. 2). In 1 patient (chemical injury), corneal graft rejection developed 11 months after penetrating keratoplasty.
Fig. 2. Anterior segment images of the patients.
A Pre-operative, B post-operative 1st year after CLAL and C Post-operative 3rd month after penetrating keratoplasty.
Discussion
Transplantation of limbal stem cells is crucial in the treatment of LSCD [15]. CLAL is one of the most preferred surgical interventions, especially in bilateral cases. Success of the limbal stem cell transplant surgery, including CLAL, have been described and interpreted differently in literature. While some authors defined surgical success as anatomical improvement in the ocular surface, some others indicated that for surgery to be regarded successful, there must be also visual improvement [14, 16]. Until recently, there was no standard criteria for defining success in limbal transplant surgery. In 2019, the ‘Limbal Stem Cell Working Group’ established a staging system to objectively identify both surgical success criteria and LSCD stage [14]. Thus, this new staging system has facilitated the diagnosis of LSCD and the evaluation of surgical outcomes in limbal stem cell transplant surgery [14]. In the present study, this objective staging system was used to assess outcomes of CLAL surgery. The improvement in the LSCD stage at the post-operative 1st year was considered to be successful, regardless of the visual acuity. Successful surgical outcomes were achieved after CLAL in 10 (52.6%) patients, which is consistent with the literature [17–20].
Although CLAL is the most preferred technique, surgical outcome of the procedure is not as decent as expected. There are several reasons of this relatively low surgical success [21]. The most important and predictable factor is immunogenic potency of the tissue [22]. The rest of the factors are still not precisely determined. Higher pre-operative LSCD stage tends to be one of the surgical failure causes. Required surgical intervention is more invasive in higher stage diseases. Thus, post-operative inflammation occurs more aggressively in these patients. Inflammation causes further limbal stem cell damage after the surgery, which may also trigger allograft failure. Consistent with the literature, in the present study, surgical success rate was found to be lower in the higher stage LSCD patients [23].
Another reason for surgical failure might be the aetiological factor causing LSCD. Chemical injuries as an aetiological factor, has lower surgical success rates in LSCD [23]. Also, alkali agents tend to have the worst surgical success rates [24, 25]. In the present study, although surgical success rate and aetiology relation was not statistically significant, in chemical burn patients CLAL surgery had poorer prognosis.
More inflammation and vascularisation may occur in chemical eye injuries compared to other aetiologies. This may increase the risk of limbal allograft failure. Therefore, some authorities recommend performing ocular surface reconstruction surgeries, after ocular surface stability and inflammation control have been achieved. In addition, patients with severe chemical burns also have a higher risk of surgical failure due to increased ocular surface inflammation [26–28]. In the present study, consistent with the literature, the longer time interval between chemical injury and CLAL surgery was associated with higher surgical success. And the degree of the chemical burn showed negative correlation with surgical success. This may suggest that any possible pre-existing inflammation, which was additionally increased by the surgery, reduces the success of the procedure.
The need for systemic immunosuppressive therapy is one of the disadvantages of limbal allograft transplantation. The allograft carries the risk of immunological rejection over a period and requires prolonged immunosuppression. Although immunosuppressants reduce the risk of graft rejection, serious complications have been reported, particularly with corticosteroids. Nevertheless, cyclosporin A and micofenolate mofetil seem to be well-tolerated for long term usage [11, 29]. No ocular or systemic complications related to long-term immunosuppressive treatment were observed in the present study.
Complicated nature of the disease itself causes additional surgical intervention requirement to limbal stem cell transplantation such as symblepharon dissection, keratoplasty, etc. [6, 8, 9]. Consistent with the literature, the most frequently performed concomitant surgical procedure with CLAL was symblepharon excision.
Long term use of topical corticosteroids may increase the risk of elevated intraocular pressure and new onset of glaucoma following CLAL. In addition, secondary glaucoma may accompany in patients with aniridia and chemical injury prior to CLAL surgery [30, 31]. Early treatment is crucial to prevent permanent optic nerve damage in these cases. Topical anti-glaucomatous therapy is usually the first step, although some patients may require surgery such as trabeculectomy, cyclophotocoagulation and glaucoma drainage device implantation [9, 12, 30–33]. Herein, elevated intraocular pressure was observed in three patients and all of them were resistant to medical therapy. For this reason, intraocular pressure was controlled by trabeculectomy in two patients and seton tube implantation in one patient.
The corneal stroma may also be affected in cases with severe LSCD. In these cases, CLAL surgery alone is usually not sufficient for the visual rehabilitation and further keratoplasty should be considered [34]. Because of the inflammation risk, immediate keratoplasty is not advised. It is recommended to wait at least 12 months following CLAL surgery for further keratoplasty surgery [35]. In the present study, keratoplasty was required in five cases to improve visual acuity. Aetiology was chemical eye injury in two of these cases and aniridia in one case. Penetrating keratoplasty was performed after controlling ocular inflammation and providing ocular surface stability. The mean time between CLAL and keratoplasty was 21.78 ± 22.58 (4.8–60) months. In all patients who underwent keratoplasty after CLAL, BCVA improvement was observed as expected.
In conclusion, despite the disadvantages such as graft rejection and the need for long-term use of immunosuppressants, CLAL is still one of the most preferred techniques in the treatment of bilateral LSCD. There is limited data in the literature on potential factors affecting surgical outcome in CLAL. Pre-operative LSCD stage and degree of chemical burn seem to be important factors influencing surgical outcome. In addition, CLAL surgery should not be rushed due to prolonged ocular surface inflammation and it should be performed when the existing inflammation subsides.
This study is one of the earlier studies which use new LSCD staging system to define post-operative success in CLAL. Although it included a relatively large number of patients compared to previous studies, the main limitations of our study were its retrospective nature and relatively short follow-up period. To better understand CLAL and to determine the surgical success rates clearly, there is a need for further prospective studies with higher number of patients.
Summary
What was known before
Despite the disadvantages such as graft rejection and the need for long-term use of immunosuppressants, CLAL is still one of the most preferred techniques in the treatment of bilateral LSCD.
What this study adds
There is limited data in the literature on potential factors affecting surgical outcome in CLAL. Pre-operative LSCD stage and degree of chemical burn seem to be important factors influencing surgical outcome. In addition, CLAL surgery should not be rushed due to prolonged ocular surface inflammation and it should be performed when the existing inflammation subsides.
Author contributions
MK, IK and OBS were responsible for the conception or design of the work. MK and IK were responsible for the data collection. MK, IK and MPO were responsible for the data analysis, MPO, SE, and AY for interpretation. MK, IK and MPO were responsible for drafting the article. MPO, SE, AY and OBS were responsible for the critical revision of the article. All authors were responsible for the final approval of the version to be published.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.