As the main source of corneal deturgescence, the corneal endothelium is critical for clear vision. Fuchs endothelial corneal dystrophy (FECD) remains the most frequent indication for corneal transplantation in the United States, accounting for approximately one-third of all transplants each year.¹ While penetrating keratoplasty (PK) was the mainstay of treatment for endothelial dysfunction in the past, selective endothelial keratoplasty (EK) surpassed PK as the most common surgical approach in 2011.¹ More recently, an endothelial “rejuvenation” technique, Descemet stripping only (DSO), has emerged as a treatment option for FECD. As a treatment with no foreign tissue, and therefore no chance of rejection and no need for chronic topical steroid therapy, DSO represents a paradigm shift in the management of corneal endothelial disease.

CORNEAL ENDOTHELIAL BIOLOGY

The corneal endothelium maintains corneal deturgescence via both a passive (barrier) function and active, ATP-requiring ionic pumps. Diseases affecting the density or function of endothelial cells typically lead to corneal swelling when enough endothelial cells are damaged. Corneal endothelial cells possess limited proliferative ability in vivo, though it is possible to induce endothelial cell mitosis in vitro.² Laboratory evidence suggests that a population of endothelial stem cells may exist. The density of the corneal endothelium decreases with age from a density of approximately 4,000 cells/mm² at birth to 2,500 cells/mm² in adulthood.² The normal endothelial mosaic consists of hexagonal cells of the same size and shape.

Endothelial cell loss results in pleomorphism (variation in cell shape) and polymegethism (variation in cell size). The corneal endothelium is also contact-inhibited, meaning that cells do not migrate once they encounter a neighboring cell.

HISTORICAL SURGICAL MANAGEMENT

Posterior lamellar keratoplasty represented the first surgical option for selective treatment of the posterior corneal layers.³ This technique, also termed deep lamellar endothelial keratoplasty, involved manual dissection of the posterior corneal stroma, Descemet membrane and the corneal endothelium with transplantation of corresponding donor tissue, also manually prepared.

In 2004, Melles et al described the descemetorhexis, which enabled removal of Descemet membrane and endothelium without posterior stroma.⁴ This technique allowed for management of endothelial disease with thinner donor tissue comprised of only a thin layer of stroma in addition to Descemet membrane and endothelium, as is utilized for Descemet stripping endothelial keratoplasty and later for Descemet stripping automated endothelial keratoplasty.⁵

Descemet membrane endothelial keratoplasty (DMEK), described only a few years later, limited the donor tissue to only Descemet membrane and endothelium, with further reduction in the rate of graft failure and the time of visual rehabilitation.⁶ The hemi-DMEK technique, described in 2018, results in similar visual outcomes to those obtained by full DMEK but requires less donor tissue.⁷ Despite the improvements in endothelial keratoplasty, there is still a need for immunosuppression with the presence of donor tissue. Additionally, the availability of donor tissue varies greatly, as there is a global shortage of donor corneas acceptable for transplantation.

DESCEMET STRIPPING ONLY

Almost 10 years ago, several lines of evidence suggested that the endothelium in FECD might retain a capacity for “self-rejuvenation.” Descemet membrane endothelial transfer, essentially a DMEK where the donor tissue did not adhere to the host cornea, produced initial corneal clearance in FECD but not in pseudophakic bullous keratopathy. This suggests that the remaining host endothelium in FECD could provide endothelial cells for corneal deturgescence.⁸ Case reports showed corneal clearance in FECD after removal of Descemet membrane without placement of donor tissue.⁹

In 2014, we began a series of deliberate Descemet stripping in FECD patients undergoing cataract surgery.¹⁰ This initial series served as a proof of concept that DSO could ameliorate symptoms of FECD, with approximately 75% of our patients achieving corneal clearance after DSO. In DSO, the central diseased endothelium is removed without subsequent placement of donor tissue, relying on migration and possibly proliferation of peripheral endothelial cells to fill the area that was surgically excised. By removing diseased endothelial cells that contact-inhibit nearby healthier endothelial cells, the defect may be filled with functional endothelium that allows for corneal clarity.

Subsequently, many other authors have contributed work in this area.¹¹ A major benefit of DSO is that donor tissue is not required, and therefore there is no need for chronic topical steroids.

CHOOSING THE RIGHT PATIENT

As more work on DSO has been published, both surgical and preoperative guidelines for success have emerged. Since corneal deturgescence relies on central migration of healthier peripheral endothelial cells, patients must not manifest limbus-to-limbus guttae. In general, the area of confluent central guttae should be less than 5 mm in diameter. The health of the peripheral endothelium can be evaluated using confocal microscopy or by using a 40x magnification on the slit lamp. The exact peripheral cell count needed for central clearance is unknown, but a cell count of 1000 cells/mm² is likely sufficient.¹²

SURGICAL TECHNIQUE MATTERS

Early series of DSO showed a success rate of approximately 75%, while later series have approached 100%.¹¹ Care should be taken to avoid damaging the posterior stroma, as this can result in corneal scarring. Although this is typically not visually significant, the surgeon will notice it postoperatively. Disruption of the posterior stroma may limit endothelial cell locomotion and eventual migration to the central cornea. Davies et al showed that by utilizing a smooth-edge tear and peel technique for Descemet membrane removal, thereby limiting involvement of the posterior stroma, their success rate increased to 100%. Finally, centration and proper sizing (generally around 4 mm in diameter) of the descemetorhexis is important for optimal visual results.

RHO-KINASE INHIBITION AND CORNEAL CLEARANCE AFTER DSO

Rho-kinase (ROCK) inhibitors are a class of topical medications typically utilized in the treatment of glaucoma. By effecting smooth muscle contraction, ROCK inhibitors are able to directly target the trabecular meshwork to allow for increased outflow and reduced IOP. The function of ROCK inhibitors is not limited to smooth muscle contraction, however, as the ROCK pathway plays a role in cell migration and even stem cell induction. By promoting endothelial migration and endothelial cell mitosis, ROCK inhibitors may play a role in cornea clearance in DSO.

Moloney et al first described two eyes in which postoperative topical administration of ripasudil resulted in corneal clearance in otherwise failed DSO.¹² The utility of ripasudil was further emphasized by Macsai et al with more rapid visual rehabilitation and improved average endothelial cell density when utilized postoperatively after DSO.¹³ Netarsudil, another ROCK inhibitor, has recently been utilized in conjunction with DSO and resulted in improvement in corneal thickness beyond the bounds of the descemetorhexis.¹⁴

Of note, we recently described that while ROCK inhibitors exhibit beneficial effects postoperatively given purposeful disruption of the endothelial cell layer, the role of ROCK inhibitors in nonsurgical management of FECD remains unclear.¹⁵ Researchers have studied combining DSO and ROCK inhibition with an intracameral injection of cultured donor endothelial cells.¹⁶ While patients in this series largely achieved corneal clarity and improved BCVA, the question of a possible summative effect of ROCK inhibition with culture donor cells remains unanswered. A multi-center, multi-national randomized, placebo-controlled study evaluating the ROCK inhibition following DSO for FECD is currently ongoing.

UNKNOWNS WITH DSO

Both patient selection and surgical technique have been dynamic in light of the relatively recent advent of DSO. While some patient factors, such as severity of disease or central corneal thickness, have certainly been associated with worse outcomes, the extent to which patient factors play a role is unclear. For example, the severity of FECD is impacted directly by increasing trinucleotide repeats in the TCF4 gene.¹⁵ It is as yet unknown whether patients with mild or moderate FECD with a higher number of repeats may experience less successful outcomes with DSO.

In prior series, we have noted a variability in time to corneal clearance, with some patients experiencing relatively rapid clarity following DSO.¹⁰ Interestingly, patients who undergo sequential DSO in the fellow eye often have similar time to corneal clearance when compared with their initial procedure. Environmental factors, such as smoking and diabetes, contribute to worsening FECD and may lead to worse outcomes with DSO, though this has not been associated with DSO failure to date.¹⁷

While ROCK inhibition appears to expedite corneal clarity and endothelial healing, level 1 evidence is currently being gathered regarding this therapy after DSO. In particular, the action of ROCK inhibition on the intact endothelium is unclear. Preliminary studies show that the ROCK pathway is involved in the eventual formation of guttae in worsening FECD. As such, topical ROCK inhibition may eventually play a role in even nonsurgical management of this disease.¹⁵

CONCLUSION

The surgical management of corneal endothelial disease has changed dramatically over the past three decades. While PK is still an important tool in the management of corneal disease, the advent of EK has minimized the rates of failure associated with donor graft rejection. DSO has allowed for management of endothelial disease while eliminating the need for donor tissue or chronic immunosuppression. With good surgical technique and proper choice of patient, this technique represents a simple, effective method for treating endothelial dysfunction from FECD.

The addition of ROCK inhibition may further improve the surgical outcomes of patients suffering from FECD. Additional research is ongoing to determine which patients will benefit most fully from this advanced treatment. OM

REFERENCES

1. Eye Bank Association of America (EBAA). 2019 Eye banking statistical report. Washington, DC: Eye Bank Association of America; 2020.
2. Joyce NC. Proliferative capacity of the corneal endothelium. Prog Retin Eye Res. 2003;22:359-389.
3. Melles GR, Lander F, Beekhuis WH, et al. Posterior lamellar keratoplasty for a case of pseudophakic bullous keratopathy. Am J Ophthalmol. 1999;127:340-341.
4. Melles GR, Wijdh RH, Nieuwendaal CP. A technique to excise the Descemet membrane from a recipient cornea (descemetorhexis). Cornea. 2004;23:286-288.
5. Gorovoy MS. Descemet-stripping automated endothelial keratoplasty. Cornea. 2006;25:886-889.
6. Price MO, Giebel AW, Fairchild KM, Price FW. Descemet’s membrane endothelial keratoplasty: prospective multicenter study of visual and refractive outcomes and endothelial survival. Ophthalmology. 2009;116:2361-2368.
7. Birbal RS, Hsien S, Zygoura V, et al. Outcomes of Hemi-Descemet Membrane Endothelial Keratoplasty for Fuchs Endothelial Corneal Dystrophy. Cornea. 2018;37:854-858.
8. Dirisamer M, Ham L, Dapena I, van Dijk K, Melles GR. Descemet membrane endothelial transfer: “free-floating” donor Descemet implantation as a potential alternative to “keratoplasty.” Cornea. 2012;31:194-197.
9. Sarnicola C, Farooq AV, Colby K. Fuchs endothelial corneal dystrophy: Update on pathogenesis and future directions. Eye Contact Lens. 2019;45:1-10.
10. Borkar DS, Veldman P, Colby KA. Treatment of Fuchs endothelial dystrophy by Descemet stripping without endothelial keratoplasty. Cornea. 2016;35:1267-1273.
11. Blitzer AL, Colby KA. Update on the surgical management of Fuchs endothelial corneal dystrophy. Ophthalmol Ther. 2020;9:757-765.
12. Moloney G, Petsoglou C, Ball M, et al. Descemetorhexis without grafting for Fuchs endothelial dystrophy-supplementation with topical ripasudil. Cornea. 2017;36:642-648.
13. Macsai MS, Shiloach M. Use of topical Rho kinase Iihibitors in the treatment of Fuchs Dystrophy after Descemet stripping only. Cornea. 2019;38:529-534.
14. Ploysangam P, Patel SP. A case report illustrating the postoperative course of descemetorhexis without endothelial keratoplasty with topical netarsudil therapy. Case Rep Ophthalmol Med. 2019;2019:6139026.
15. Kinoshita S, Colby K, Kruse F. A close look at the clinical efficacy of Rho-associated protein kinase inhibitor eye drops for Fuchs endothelial corneal dystrophy. Cornea. Feb. 4, 2021. Volume published ahead of print.
16. Kinoshita S, Koizumi N, Ueno M, et al. Injection of cultured cells with a ROCK inhibitor for bullous keratopathy. N Engl J Med. 2018;378:995-1003.
17. Zhang X, Igo RP Jr, Fondran J, et al; Fuchs’ Genetics Multi-Center Study Group. Association of smoking and other risk factors with Fuchs’ endothelial corneal dystrophy severity and corneal thickness. Invest Ophthalmol Vis Sci. 2013;54:5829-5835.

About the Authors

Dylan Stevens, MD, is a second-year ophthalmology resident at New York University. With a drive towards a career in corneal and external disease, Dr. Stevens takes part in the surgical and medical management of a wide range of pathology present in New York City.

Kathryn Colby, MD, PhD, is an academic cornea specialist who currently serves as the chair of the Department of Ophthalmology at New York University. One of the pioneers of Descemet stripping only, Dr. Colby continues to develop and refine this technique for the management of corneal endothelial disease. Contact her at Kathryn.Colby@nyulangone.org.

Disclosure: The authors report no relevant financial relationships.