Chemical injury of the ocular surface is a significant public health problem with a serious economic effect due to prolonged hospitalization, long-term medical treatment, multiple surgery requirement, work-day loss, and even blindness. In severe ocular chemical injury, the main cause of blindness is LSCD. The current and definitive treatment of LSCD is the replacement of healthy limbal stem cells.[7, 16, 17]
Young male individuals are at a higher risk of ocular chemical injuries as well as other traumas, especially due to work accidents.[18, 19] In accordance with the literature, in the present study the majority of the patients (n = 57,71.2%) were male and the mean age of the patients was 37.9 ± 15.7.
In chemical ocular surface injury, exposure to alkaline agents is reported to be more frequent than acid agents.[6, 21] In the present study, 56.3% of the overall injuries were caused by alkaline substances in consistent with the literature.
The severity of the injury generally depends on exposure time and type of chemical agent. Potent corrosive agents (mostly alkaline substances) may penetrate deeper in the eye. Therefore, it develops prolonged inflammation not only on the ocular surface, but also in deeper structures causing more severe LSCD and other complications such as glaucoma and cataract formation.[22, 23] In the present study, the eyes with higher chemical injury grades tend to have higher LSCD stages.
For evaluating the surgical success, different success criteria for LSCT were defined among literature. While some authorities described the anatomical improvement in ocular surface as surgical success; in other studies, functional improvement and the patient-reported symptoms are used to evaluate surgical success. In a recent meta-analysis including 40 clinical studies (2202 eyes), the overall success rate of all LSCT was found to be 67.4%, and improvement rate of ocular surface was found to be 74.5%. Furthermore, the lack of standardized criteria for evaluation of LSCD made it difficult to compare the outcomes of different treatment modalities. Although the increase in visual acuity was considered as a success criterion in most previous studies, LSCT actually aims to treat LSCD findings, not to improve the vision. Stromal opacities are the main cause of poor vision in patients with severe ocular chemical injury, so the absence of visual improvement does not actually indicate any treatment failure.[14, 24, 25] Recently in 2019, ‘Limbal Stem Cell Working Group’ established an objective scale to evaluate LSCD. This staging system provided insight not only in evaluating surgical success, but also in the diagnosis and definition of LSCD, and determination of the appropriate treatment option.
There are several surgical intervention options for LSCD. Limbal autograft is the most commonly performed surgical option in unilateral cases.[25–27] In consistence with the literature, limbal autograft was the most common surgical intervention in the present study.
Surgery type is one of the most important factors that affects success rate. Many different techniques have been described according to the source of the cells and the carrier tissue. While limbal autograft is generally preferred in unilateral LSCD; in bilateral cases, limbal allograft is needed. The main disadvantages of limbal autograft are unrepeatability and LSCD risk at the contralateral healthy eye. In limbal allograft, there are main problems such as risk of rejection and requirement of systemic immunosuppressive therapy use. CLET, on the other hand, is a relatively new and promising method with a success rate of approximately 80%. While repeatability is the most important advantage of CLET, the main disadvantage is the procedures’ expensive nature. In a meta-analysis including 40 clinical studies (2202 eyes), improvement of the ocular surface was 85.7% (33–100%) for limbal autograft, 57.8% (0–89) for limbal allograft and 84.7% (44–91) for CLET. Herein, surgical success rates at the post-operative 1st year were; 65.5% for limbal autograft, 41.7% for limbal allograft and 90% for CLET. The improvement in postoperative LSCD stage was statistically higher in the CLET. Although there was no difference between three groups in respect to nature of the chemical agent, chemical injury grades and preoperative LSCD stages, the time interval between injury and limbal transplantation was significantly longer in CLET group. These results suggest that the successful surgical results of CLET may be associated with the longer time interval between chemical injury and LSCT surgery due to the inflammation regression by time, which provides the limbal graft survival better.
It is known that different factors may also affect LSCT outcomes, beside the surgery type. Cheng et al. reported that preoperative symblepharon grade and presence of inflammation both play a significant role in CLET outcomes. In their series with 80 eyes with symblepharon secondary to chemical or thermal injury; success rate of CLET was higher in eyes with grade 1/2 symblepharon than eyes with grade 3 and 4 symblepharon. El-hofi et al. reported better final BCVA results after limbal allograft in Dua-Grade 4 chemical injury than in Dua-Grade 5 chemical injury. In their study with 20 chemical injury patients who underwent limbal allograft, all patients that needed regrafting were Dua-Grade 5. They also reported that all eyes with delayed re-epithelization after limbal transplantation were alkali injury. However, in the present study, there was no significant relationship between gender, age, nature of chemical agent (alkaline/acid/other), presence of symblepharon and chemical injury grade with post-operative 1st year surgical success rates.
It is known that the inflammation is the main cause of graft failure in LSCT. And in the subacute phase of chemical injury, a low degree of inflammation may persist despite the use of anti-inflammatory therapy. Therefore, most of the authorities have indicated that performing LSCT in the chronic period of chemical injury is much better for graft survival.[23, 33] However, publications showing the direct effect of LSCT timing on LSCT outcomes are limited, and the ideal timing of LSCT after chemical injury has not been determined. Rao et al. indicated that surgery at the acute phase of injury (< 4 months) is associated with delayed corneal re-epithelialization and poorer visual outcomes. Sejpal et al. reported a high failure rate in eyes who underwent CLET within 4 months after chemical injury. On the contrary, Ozdemir et al. stated that early LSCT may prevent corneal neovascularization in chemical injury with large epithelial defects and small limbal ischemia. Herein, with 80 eyes, the longer interval between injury and transplantation was associated with the higher surgical success rates.
Also, the pre-operative LSCD stage may also be associated with the prognosis after LSCT. Due to the lack of LSCD grading consensus, there was not any detailed study that evaluates the pre- and post-operative LSCD grading association. In the present study, although lower LSCD stages at the initial examination was tent to have better surgical outcomes at 1st year, the statistical difference was not significant. To the best of our knowledge, this study will be one of the earlier studies, which accurately demonstrates the relationship between pre-operative LSCD stages and LSCT success by using the staging system established by ‘Limbal Stem Cell Working Group’.
LSCT is an effective treatment for ocular chemical injury where only the corneal epithelium and limbus are affected. It provides ocular integrity and improves visual acuity. However, if the corneal stroma is affected, PK is required for visual improvement. PK simultaneously with LSCT is solely preferred in the presence of corneal perforation, since it has a high graft failure rate.[38, 39] It is known that the presence of inflammation and vascularization in the recipient bed increases the risk of rejection of the corneal graft. Therefore, it is recommended to perform PK once ocular surface stability is achieved with LSCT. Although there is no consensus about ideal timing of PK after LSCT, it is recommended to be performed at least 12 months later. In addition, there is limited information in the literature regarding the potential effect of PK on limbal graft survival. Figuerdo et al. recommended performing PK at least 12 months following CLET. They reported that performing PK at least 12 months after CLET did not negatively affect CLET survival and provided significant improvement in visual acuity. In the present study, 11 of 80 patients underwent PK after LSCT, and the mean time between LSCT and PK was found to be 22.4 months. None of the patients had worsening of LSCD stage and BCVA after PK. Although the number of patients who underwent PK was limited, it was enough to show that PK did not affect limbal graft survival. In 10 out of 11 patients, a significant increase in BCVA was achieved following PK. The increase in BCVA after PK was found to be higher in those with an advanced initial LSCD stage. In LSCD staging, involvement of the central 5 mm zone of the cornea was stated as the most important criteria. The LSCD stage is expected to be high in patients with central corneal involvement. So, in patients with effected central cornea, better visual acuity will be achieved after PK.
Although the main limitations of the study are its retrospective nature and the limited number of patients in the CLET and limbal allograft groups, the results of the current study are remarkable to highlight the impact of the novel LSCD grading system.
In conclusion, LSCT is the surgical treatment of severe ocular chemical injuries that cause LSCD. It is vital to determine the stage of the LSCD accurately in order to evaluate the surgical success rate. The most important factors affecting the outcomes of LSCT are, the method of transplantation and the time between surgery and injury. For this reason, in order to achieve higher success rates, rushing surgeries following chemical injury should be avoided.