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Graftless Corneal Endothelial Replacement s CORNEA GRAFTLESS CORNEAL ENDOTHELIAL REPLACEMENT A new treatment paradigm in Fuchs dystrophy. BY LAIYIN MA, MD; AND ANGIE WEN, MD Courtesy of Kathryn Colby, MD, PhD he innermost layer of the dystrophy, according to Patricia cornea, the endothelium, Dahl, CEO at The Eye-Bank for Sight maintains corneal clarity by Restoration in New York (written serving as a barrier to aqueous communication, February 2020). humor and functioning as a Although the surgical management metabolicT pump to remove excess of FECD is widely accepted, these fluid from the stroma. A normal procedures are invasive, healing time human endothelial cell count at is often prolonged, and complications birth is 4,000 to 5,000 cells/mm2. such as allograft rejection and That figure decreases progressively detachment can occur. Additionally, with age by about 0.6% per year.1 there is a global shortage of corneal Figure. Five years after DSO. This rate of cellular decline can be graft tissue, with only one cornea compounded by damage secondary available for every 70 needed.5 topical ROCK inhibitors are potent to eye surgery, trauma, or diseases Investigators around the world are enhancers of corneal endothelial of the endothelium, the most therefore avidly searching for graftless wound healing because they promote common of which is Fuchs treatment options for FECD. the proliferation of residual healthy endothelial corneal dystrophy (FECD). endothelial cells peripheral to the site When cell density drops below RHO-ASSOCIATED KINASE INHIBITORS of injury.8 about 500 cells/mm2, endothelial Rho-associated kinase (ROCK) The use of ROCK inhibitors in the compromise results in corneal edema, inhibitors are one promising adjunct medical management of FECD was first clouding, and decreased vision.2 for FECD treatment. ROCK-signaling reported in 2013, when Koizumi and First described by Ernst Fuchs in pathways are responsible for a broad colleagues described the successful 1910, FECD is a degenerative disease of spectrum of fundamental cellular treatment of a 52-year-old Japanese the corneal endothelium that results events, and these pathways have man. Treatment consisted of denuding in cell dysmorphia and dysfunction.3 become important therapeutic the central corneal endothelium and The surgical management of FECD targets in the treatment of many applying a ROCK inhibitor topically usually entails replacing the diseased pathophysiologic conditions (see for 1 week. The patient’s bullous endothelium via Descemet stripping Use of ROCK Inhibitors in Other Areas keratopathy resolved; the cornea automated endothelial keratoplasty of Medicine).6 Cellular stresses on remained clear at 2 years, and visual or Descemet membrane endothelial the corneal endothelium activate acuity was 20/20.9 keratoplasty. In the United States, the Rho/ROCK/myosin light chain In 2018, the same investigators FECD is an increasingly common phosphorylation pathway, which reported successfully treating bullous indication for corneal transplantation, decreases cell adhesion to the keratopathy from various causes with accounting for almost one-third of underlying extracellular matrix and intracameral injections of cultured all transplants performed in 2017.4 activates the apoptosis cycle.7 ROCK human corneal endothelial cells This number is on the rise. In 2018, inhibition suppresses myosin light suspended in a solution with a ROCK more than 50% of all endothelial chain phosphorylation, discourages inhibitor. Descemet membrane was keratoplasties in the United States apoptosis, and counteracts the stripped from the central 8-mm– were performed for endothelial loss of cell adhesion.7 Additionally, diameter area of the cornea prior to 24 CATARACT & REFRACTIVE SURGERY TODAY | MAY 2020 CORNEA s injection, and the patients remained Descemet membrane can release greater than 625 µm was associated in a prone position for 3 hours to contact inhibition and facilitate with reduced corneal clearance after enhance adhesion of the injected cells. the central migration of healthier DSO in her initial series. Dr. Colby Six months after the injections, corneal peripheral endothelial cells.15 said she examines the peripheral transparency had been restored Borkar and colleagues evaluated endothelium to ensure that it is to 100% of the treated eyes, and 13 eyes of 11 patients with FECD and healthy and without significant guttae endothelial density was greater than no countable central endothelial because these cells will repopulate 500 cells/mm2.10 cells preoperatively who underwent the area of stripped cells centrally. She DSO with stripping of the central prefers the peripheral cell density to be DESCEMET STRIPPING WITHOUT 4-mm–diameter area of endothelium. greater than 1,500 cells/mm2, whereas ENDOTHELIAL KERATOPLASTY The corneas of four of these eyes Moloney has found a peripheral cell Corneal endothelial cells have an cleared by postoperative month 1. density greater than 1,000 cells/mm2 extremely limited ability to proliferate Clearing occurred in another four to be sufficient.17 The visual status of in vivo. Instead, neighboring cells eyes by month 3 and in two eyes the fellow eye is another important compensate for endothelial cell by month 6. Three eyes eventually consideration during surgical planning loss by enlarging and spreading required endothelial keratoplasty.13 because an initial decline in vision after to cover the defects.11 Since 2013, Iovieno et al reported clearance in four DSO is expected. Patients should be several researchers have reported of five eyes that underwent DSO with counseled preoperatively that visual observing corneal clearing after a 4-mm descemetorhexis.16 recovery will be gradual and is not iatrogenic endothelial trauma, which Although it is not well understood guaranteed. gave rise to the idea of healing by what causes certain patients to be Restricting the descemetorhexis to primary intention as a planned fast responders, responders, slow the central 4 mm seems to promote surgical strategy.12-14 A procedure responders, or nonresponders after a higher rate of corneal clearance dubbed Descemet membrane stripping DSO—terminology coined by Kathryn by limiting the surface area that the only (DSO) involves performing Colby, MD, PhD—experience suggests remaining endothelial cells are asked a descemetorhexis without that surgical technique and patient to repopulate. Initial series using a transplantation of a donor graft selection are two keys to successful larger descemetorhexis (8 mm in a (Figure); this is the newest proposed DSO.13 When we spoke to Dr. Colby study by Bleyen et al18 and 6 mm surgical treatment for FECD. The for this article, she stated that a in a study by Koenig19) were largely theory is that removing the diseased preoperative pachymetry reading disappointing. Of note, increasing the descemetorhexis from 4 to 6 mm in diameter more than doubles the surface area of stripped cells USE OF ROCK INHIBITORS IN OTHER AREAS OF MEDICINE (9/4 = 2.25).13 Rho-associated kinase (ROCK) inhibition is being analogues and/or adrenergic beta-receptor It is important to avoid surgical studied extensively for the treatment of a variety antagonists. The most commonly observed adverse trauma during Descemet stripping of diseases, including asthma, cancer, erectile effect is conjunctival hyperemia.2 because trauma can elicit a fibrotic dysfunction, glaucoma, insulin resistance, kidney In the United States, two formulations of ROCK scarring response that will challenge the central migration of peripheral failure, neuronal degeneration, and osteoporosis. inhibitor ophthalmic solutions are available for the endothelial cells. Davies and colleagues In 1995, the ROCK inhibitor fasudil hydrochloride reduction of elevated IOP in patients with open-angle described a descemetorhexis hydrate was approved in China and Japan for the glaucoma or ocular hypertension. The FDA approved technique that minimizes scarring to treatment of cerebral vasospasm through cerebral netarsudil ophthalmic solution 0.02% (Rhopressa, 1 3 the corneal stroma: a Fogla Descemet vasodilation. Aerie Pharmaceuticals) in 2017. In 2019, the FDA membrane–stripping hook is used to Ripasudil hydrochloride hydrate 0.4% (Glanatec, approved netarsudil 0.02%/latanoprost ophthalmic score only 2 clock hours, and the rest 4 Kowa, not available in the United States) was solution 0.005% (Rocklatan, Aerie Pharmaceuticals). of the descemetorhexis is peeled using the first ROCK inhibitor approved in any country forceps.20 1. Hu E, Lee D. Rho kinase as potential therapeutic target for cardiovascular for clinical use for the treatment of glaucoma diseases: opportunities and challenges. Expert Opin Ther Targets. 2005;9(4): and ocular hypertension. Ripasudil lowers IOP 715-736. COMBINING DSO WITH A 2. Tanihara H, Inoue T, Yamamoto T, et al; K-115 Clinical Study Group. Intra- by increasing aqueous humor outflow through ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115), over ROCK INHIBITOR the conventional pathway. Clinical trials have 24 hours in primary open-angle glaucoma and ocular hypertension: a random- Moloney et al used ripasudil 0.4% ized, open-label, crossover study. Acta Ophthalmol. 2015;93(4):e254-260. confirmed the efficacy of ripasudil as monotherapy 3. Rhopressa [package insert]. Irvine, CA: Aerie Pharmaceuticals, Inc.; 2017. (Glanatec, Kowa, not available in or as an adjunctive medication to prostaglandin 4. Rocklatan [package insert]. Irvine, CA: Aerie Pharmaceuticals, Inc.; 2019. the United States), a ROCK
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