Long-term outcome of cultured corneal endothelial cell transplantation with descemetorhexis: A 10-year follow-up study

Abstract

Purpose

To describe the 10-year clinical course after cultured human corneal endothelial cell (CEC) (cHCEC) transplantation combined with central descemetorhexis in a single patient with Fuchs endothelial corneal dystrophy (FECD).

Observations

A 49-year-old Japanese male was referred to the Department of Ophthalmology at Kyoto Prefectural University of Medicine, Kyoto, Japan in 2013 due to decreased visual acuity (VA) and CEC loss in his left eye caused by FECD. Upon examination, FECD-related central corneal edema, cataract, and decreased VA were observed, and on September 4, 2014 the patient underwent cHCEC transplantation in his left eye. Intraoperatively, a Descemet membrane (DM) tear occurred while abnormal CECs were being removed, thus requiring a change in the surgical plan. Subsequently, the DM was completely stripped (descemetorhexis) in an approximately 5-mm-diameter area including the pupillary center, followed by cHCEC transplantation into the anterior chamber. Prior to surgery, best-corrected VA (BCVA) was 20/50 and central corneal thickness (CCT) was 637 μm, yet corneal transparency was restored and BCVA improved to 20/20 at 6-months postoperative. At 10-years postoperative, a reasonable CEC density (CECD) was found to have adhered to the descemetorhexis area, with maintained corneal transparency; i.e., CCT measured 548 μm, CECD in the central area was 938 cells/mm², and BCVA remained stable at 20/13.

Conclusion and importance

While prospective studies are needed to generalize safety and efficacy, this FECD case treated with cHCEC transplantation combined with descemetorhexis showed no serious adverse events and sustained corneal clarity with stable CECD and CCT.

1. Introduction

Fuchs endothelial corneal dystrophy (FECD) is a genetically related disorder characterized by the progressive accumulation of extracellular matrix (ECM) deposits called guttae on and within the Descemet membrane (DM), which eventually leads to a marked decrease in corneal endothelial cells (CECs), corneal edema, and reduction of visual acuity (VA).^1,2 Recent advancements in corneal endothelial transplantation techniques have now enabled selective transplantation of CECs in patients afflicted with FECD, and Descemet stripping automated endothelial keratoplasty (DSAEK) and DM endothelial keratoplasty (DMEK) are now widely performed.^3,4 These surgical procedures result in improved VA via removal of the thickened DM, an increase in CEC density (CECD) and function, an enhancement of donor graft survival, and a reduction of complications.⁵ However, the global shortage of donor eyes and concerns regarding long-term corneal graft survival remain significant challenges.⁶ Descemet stripping only (DSO), i.e., without the use of a donor corneal graft, has also been proposed for the treatment of early-phase FECD.

As a novel strategy to address these issues, we recently developed a cultured human CEC (cHCEC) transplantation (i.e., injection) procedure.⁷ Typically, our novel method preserves the host's DM, which serves as a scaffold for the transplanted cHCECs and helps promote cell adhesion and functional restoration of vision. Long-term prospective data further supports the safety and durability of cHCEC transplantation, with sustained corneal clarity and stable endothelial profiles.8, 9, 10 However, the abnormal DM with guttae in FECD cases can, itself, limit the potential of the surgery to restore vision.^11,12 Although combining cHCEC transplantation (injection) with central DM removal (descemetorhexis) has been found to be feasible in preclinical rabbit models,¹³ the long-term clinical outcomes of such a combined procedure in humans has yet to be fully elucidated.

In this report, we present a unique case of a male Japanese FECD patient in whom an intraoperative DM tear necessitated central descemetorhexis prior to cHCEC injection. We followed this patient for over 10-years postoperative, and found that the cornea remained clear with stable VA, a normal central corneal thickness (CCT), and long-term CEC survival.

2. Case report

A 49-year-old Japanese male was referred to the Department of Ophthalmology at Kyoto Prefectural University of Medicine, Kyoto, Japan in 2013 due to decreased VA and CEC loss in his left eye caused by FECD. At the initial examination, CEC dysfunction, corneal edema predominantly distributed in the central region with guttae, and reduced VA associated with cataract were observed in his left eye. Cataract surgery was subsequently performed in that eye, and on September 4, 2014 he underwent cHCEC transplantation in that eye. Preoperative examinations showed a best-corrected VA (BCVA) of 20/50, and a CCT of 637 μm. CECs were not detected by specular microscopy. The surgery was performed using an irrigation solution to maintain the anterior chamber. Briefly, the abnormal ECM and degenerated cells on the DM were first removed by gentle mechanical polishing using a silicone needle (Inami & Co., Ltd., Tokyo, Japan) within an 8-mm-diameter area of the central cornea. During the mechanical polishing, a DM tear occurred near the center of the cornea; after recognizing the tear, a separate paracentesis was created and continuous irrigation through this port was used to stabilize the anterior chamber while the Kinoshita Descemetorhexis Forceps (Eye Technology Inc.) were used to grasp the tear edge and complete a controlled circumferential descemetorhexis to a 5-mm-diameter circular area centered on the pupil. Next, a suspension of cHCECs (300 μL containing 1 million cells) prepared in modified Opti-MEM I supplemented with the ROCK inhibitor Y-27632 at a final concentration of 100 μM was injected into the anterior chamber via the use of a 26-gauge needle. Following surgery, the patient was immediately placed in a prone position for 3 hours to enhance the adhesion of the transplanted cells. At 9-years postoperative, the treated eye underwent Nd:YAG laser capsulotomy for posterior capsule opacification, and at the 10-year follow-up examination, the BCVA in his left eye had improved to 20/13, the CCT had decreased to 548 μm, and the CECD in the central and peripheral area was 938 and 859 cells/mm² relatively (Fig. 1, Fig. 2). Moreover, at 10-years postoperative, specular microscopy images obtained via the use of a slit-scanning contact specular microscope (CellChek®; Konan Medical, Inc., Nishinomiya, Japan) revealed that the CECs were well attached and viable on the entire posterior corneal surface, including the area in which descemetorhexis was performed. The demarcation line of the descemetorhexis surgery was clearly observed, and no new guttae were observed inside the descemetorhexis area (Fig. 2). In addition, no episodes of graft rejection occurred throughout the 10-year follow-up period.

Fig. 1.

Slit-lamp photographs and Scheimpflug images. The left eye of a patient with Fuchs endothelial corneal dystrophy (FECD) before and after cultured human corneal endothelial cell (CEC) (cHCEC) transplantation (injection). Preoperative images (A, B) show corneal edema, with a central corneal thickness (CCT) of 637 μm. At 3-years postoperative (C, D), corneal transparency was restored, with a CCT of 544 μm. At 10-years postoperative (E, F), corneal clarity remained, with a CCT of 548 μm and excellent visual acuity (VA) (20/13).

Fig. 2.

CECs in and around the descemetorhexis area. CECs can be seen without guttae formation within the 5-mm-diameter descemetorhexis zone where the Descemet membrane (DM) was removed during surgery. Panels A and B show the descemetorhexis zone at 3- and 10-years postoperative, respectively, with the descemetorhexis area indicated by a dotted line. The red dotted lines indicate the location of corneal endothelial cell images within the descemetorhexis zone, while the yellow dotted lines denote the location of corneal endothelial cell images outside the descemetorhexis zone. Panels C and D present central specular microscopy images obtained within the descemetorhexis area (over bare stroma without DM) at 3- and 10-years postoperative, respectively. Panels E and F present representative peripheral specular microscopy images acquired outside the descemetorhexis margin (over intact DM) at 3- and 10-years postoperative, respectively. Across both central and peripheral regions, cells exhibited a predominantly hexagonal morphology with reasonable density, with little difference between the central and peripheral regions.

3. Discussion

3.1. Summary of the primary findings

The findings in this report document, for the first time, a decade-long preservation of corneal clarity and 20/13 vision following cHCEC transplantation combined with descemetorhexis in a patient with FECD. At 10-years postoperative, the graft sustained a CECD of 938 cells/mm² and a CCT of 548 μm, with no rejection episodes or secondary corneal interventions required.

3.2. Comparison with existing literature

The outcomes in this case did not suggest an evident disadvantage when viewed against published outcomes for DSO and endothelial keratoplasty. Recent DSO studies have reported success rates ranging from 60 to 85 % at 1–2 years,14, 15, 16, 17, 18, 19 with many cases requiring Rho-associated kinase (ROCK)-inhibitor supplementation to achieve corneal clearance. Furthermore, the guttae were observed to recur postoperatively. In contrast, the treated eye in our patient achieved and maintained excellent VA without any pharmacological supplementation, and no postoperative guttae developed. This finding aligns with our previous report that cHCEC transplantation did not increase guttae over 3 years in FECD eyes after polishing of abnormal ECM and/or degenerated CECs.²⁰ When compared with DMEK outcomes, which show approximately 60–70 % CEC loss at 10 years,^21,22 the case in this study demonstrated remarkable stability with minimal progressive CEC loss over 10 years (Fig. 3). The combination of cHCEC transplantation with descemetorhexis provided both a clear central optical zone and exogenous cell supplementation, and may offer an advantage over DSO, which relies entirely on the migration of the patient's own peripheral cells to repopulate the central cornea, potentially allowing for the recurrence of guttae.²³ In cHCEC transplantation, abnormal cells were polished during the surgical procedure prior to cell injection. Consequently, the cells in the descemetorhexis region were primarily transplanted mature differentiated cells, with peripheral cell proliferation being minimal.²⁴ Conversely, cHCECs transplanted into the anterior chamber in the absence of the DM were able to repopulate the bare posterior surface of the corneal stroma and presumably secrete a newly formed DM, as was observed in the previous animal studies.

Fig. 3.

Clinical outcomes over the 10-year period. Postoperative follow-up clinical data of the CCT and CEC density (CECD) (A) and best-corrected VA (BCVA) (B). Post transplantation, CCT was maintained at around 550 μm and CEC loss was minimal. Post surgery, BCVA improved from 20/50 to better than 20/20, with a temporary decline in 2023 due to posterior capsule opacification (treated with Nd:YAG laser capsulotomy), and a final BCVA of 20/13.

3.3. Clinical implications

As previously reported, mechanical polishing of the DM was insufficient to remove guttae in approximately 33 % of FECD patients undergoing cHCEC transplantation, although the remaining two-thirds of the patients achieved excellent postoperative VA with a relatively smooth posterior surface.²⁰ The findings of this current long-term case report suggest a new therapeutic strategy for selective cases of FECD with a thickened DM and dense guttae; i.e., descemetorhexis combined with cHCEC transplantation. Further studies are warranted to compare the outcomes of cHCEC injection therapy with and without descemetorhexis in cases of severe FECD, and rather than considering the DM as an indispensable basement membrane, selective removal of the diseased membrane combined with cell therapy may yield superior outcomes in such cases. This surgical approach may be particularly valuable in FECD patients with central guttae limiting visual potential, failed DSO cases requiring cellular supplementation, and eyes with a localized DM pathology.

3.4. Limitations and future directions

It should be noted that this report had several limitations. First, this single long-term case study cannot establish generalizable treatment protocols. Although unexpected, the nature of the accidental DM tear obviously prevents systematic evaluation of planned descemetorhexis procedures. Second, the optimal extent of DM removal, the cell dosing, and patient selection criteria remain undefined. Moreover, as a single-case report, the data supporting safety and efficacy are insufficient. Hence, future research should prioritize prospective trials to address these questions.

4. Conclusion

In this single case, cHCEC transplantation combined with descemetorhexis was associated with sustained corneal clarity and good visual function through 10 years of follow-up without serious adverse events.

CRediT authorship contribution statement

Yuto Kataoka: Writing – original draft, Visualization, Data curation, Conceptualization. Yasufumi Tomioka: Writing – review & editing. Morio Ueno: Writing – review & editing. Koji Kitazawa: Writing – review & editing. Hideki Fukuoka: Writing – review & editing. Naoki Okumura: Writing – review & editing. Noriko Koizumi: Writing – review & editing. Chie Sotozono: Writing – review & editing, Supervision. Shigeru Kinoshita: Writing – review & editing, Supervision.

Statement of ethics

The subject has given his written informed consent to publish his case (including publication of images). The protocols of this study were approved by the Institutional Review Board and the Ethics Committee of Kyoto Prefectural University of Medicine (Approval No. RBMR-R-31-4 and ERB-C-1376-4), and all procedures were performed ethically in accordance with the tenets set forth in the Declaration of Helsinki.

Authorship

All authors attest that they meet the current ICMJE criteria.

Funding/support

None to report.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.