The recent emergence of selective keratoplasties has been a revolutionary development in the treatment of corneal diseases that would have previously mandated a full-thickness corneal transplant.
For example, the ability to now replace only damaged endothelial corneal tissue via Descemet’s stripping endothelial keratoplasty (DSEK), or sometimes Descemet’s membrane endothelial keratoplasty (DMEK), has resulted in improved visual outcomes at a much faster rate than previously possible.
Because of this quantum leap forward, the procedure has been widely adopted by corneal surgeons over the past few years, accounting for more than 30% of all grafts performed in the United States in 2009.1
In 2011, 48% of all endothelial keratoplasties were performed as a result of Fuchs’ dystrophy.2
However, despite all of the successes as a result of the procedure, there are always short- and long-term risks inherent with any surgery. Infection, graft failure, rejection and cell loss all are possible complications of endothelial keratoplasty.3
Additionally, there are shortages of available and viable tissue in many countries around the world.
The safety and visual acuity improvements of DSEK/DMEK and related procedures have been profound. But another revolution in endothelial dystrophy may soon follow.
Rethinking Endothelial Disease
What if we had the ability to treat this devastating condition, in office, with a short course of a topical eye drop that allows healing of the damaged endothelial cells, while at the same time regenerating healthy endothelial cells?
Some ongoing research suggests that this actually may one day be a possibility.
The corneal endothelium, a non-replicating monolayer of cells, is responsible for the passive diffusion of nutrients from the aqueous, as well as the hydration and clarity of the cornea through its pump and barrier functions.4 Any damage or defect caused to this structure results in a compensatory migration and enlargement of the remaining cells, as well as a loss of pump function.
This then causes a loss of transparency and decreased visual acuity. Rho-associated kinase (ROCK) inhibitor is a serine/threonine kinase, which mediates the formation of RhoA-induced stress fibers and focal adhesions.5 The Rho/ROCK pathway is involved in regulating the cytoskeleton, cell migration, cell apoptosis and cell proliferation.6
A group of researchers from Japan, led by Naoki Okumara, MD, have extensively studied the use of ROCK inhibitors to promote corneal endothelial wound healing in both primate and human eyes.
In 2009 they reported that ROCK inhibitor Y-27632 promoted the adhesion of corneal endothelial cells, inhibited apoptosis and increased the number of proliferating cells in primates.7 They have since studied the use of this specific inhibitor for the pharmacological treatment of human endothelial disease, early stages of Fuchs’ dystrophy and postsurgical trauma.8-9
During their studies, the researchers created endothelial damage in rabbits (who display endothelial proliferation superior to humans) and in cynomolgus monkeys (whose ability to proliferate endothelium is as limited as humans) via transcorneal freezing.
In the primate study, 10mm of ROCK inhibitor Y-27632 was applied topically six times daily for 48 hours in one eye, while the other eye was used as a control. The endothelial cell density was measured four weeks following treatment via noncontact specular microscopy.
Figure 1. Fuchs' corneal dystrophy.
Credit: Jennifer Harthan, OD
An enlargement of the remaining neighboring endothelial cells with diminished cell density (~1500 cells/mm2) was observed in the control group, while the group treated with ROCK inhibitor Y-27632 exhibited non-compensatory cell size enlargement and an endothelial cell density of ~3000 cells/mm2.
They postulate that this may be caused by proliferation of the undamaged peripheral cells. Additionally, when compared to the control group, the eyes treated with ROCK inhibitor Y-27632 showed enhanced functional recovery of both their barrier and pump functions.
The investigators treated eight human corneas concurrently with the primate study—four with central corneal edema and four with diffuse corneal edema. All of the human corneas were classified as “late-stage Fuchs’ corneal dystrophy.”
The subjects’ endothelial cells were exposed to transcorneal freezing for 15 seconds, followed by the application of one drop of 10mm of Y-27632 six times daily over the course of seven days. Additionally, gatifloxacin 0.3% hydrate antibiotic eye drops were used four times a day.
Slit-lamp exam, noncontact specular microscopy, anterior segment OCT and intraocular pressure were performed daily for seven days. These tests were then repeated every week for one month, followed by every four weeks up to six months.
In the patients with central corneal edema, center thickness was reduced six months after treatment compared to baseline at presentation, with neither a decrease in visual acuity nor any eyedrop-related complications. No difference in corneal thickness was noted in the eyes with diffuse cornea edema.
One of these patients—a 52-year-old man with Fuchs’ dystrophy referred to the study authors for surgery—was reported on in a recent paper.10
His best-corrected visual acuity was 20/63, central corneal thickness was 703um and endothelial cell density was 757 cells/mm2. After transcorneal freezing and the above described protocol of treatment, visual acuity improved to 20/20 just two weeks following treatment.
Six months later, corneal thickness had reduced to 568um, with an increased average corneal cell density of 1549.3 +/-89.7 centrally and 705 +/-61.1 peripherally. Two years post-treatment, visual acuity remains 20/16 with complete corneal clarity.
The use of transcorneal freezing in the area of the diseased cornea, in conjunction with topically applied ROCK inhibitor therapy, could potentially be a tremendous leap forward in the non-surgical treatment of endothelial corneal disease.
With only a limited case series and no statistically significant data currently reported, however, further research with larger cohorts of patients is still required to determine if this will be a clinically viable procedure.
The topic is currently generating great deal of interest amongst corneal surgeons who are searching for alternatives to costly and technically challenging surgical procedures. Patients who are reluctant to undergo surgery may also benefit from this treatment option.
This technique has the potential to offer eye care providers another exciting option for our Fuchs’ dystrophy or bullous keratopathy patients.
1. Li JY, Mannis MJ. Eye banking and the changing trends in contemporary corneal surgery. Int Ophthalmol Clinic. 2010;50(3):101-12.
2. Eye Bank Association of America, 2011. Eye banking statistical report Available from http:www.corneas.org/repository/omages/pressimages/EBAA 2011 Statistical Report- Final.pdf.
3. Price MO, Gorovoy M, Price FW Jr, Benetz BA et al. Descemet’s stripping automated endothelial keratoplasty: three-year graft and endothelial cell survival compared with penetrating keratoplasty. Ophthalmology. 2013 Feb;120(2):246-51
.4. Mishima S. Clinical investigations on the corneal endothelium. Ophthalmology. 1982 Jun;89(6):525-30.
5.Anderson S, DiCesare L, Tan I, Leung T, SundarRaj N. Rho-mediated assembly of stress fibers is differentially regulated in corneal fibroblasts and myofibroblasts. Exp Cell Res. 2004 Aug 15;298(2):574-83.
6. Riento K, Ridley AJ. ROCKS; multifunctional kinases in cell behavior. Nat Rev Mol. Cell Biol. (6):446-456.
7. Hirata K, Hamuro J, Kinoshita S. Enhancement on primate corneal endothelial cell survival in vitro by a ROCK inhibitor. Invest Ophthalmol Vis Sci. 2009 Aug;50(8):3680-7.
8. Okumura N, Koizumi N, Ueno M, Sakamoto Y, et al. Enhancement of corneal endothelium wound healing by Rho-associated kinase (ROCK) inhibitor eye drops Br J Ophthalmol. 2011 Jul;95(7):1006-9.
9. Okumura N, Koizumi N, Kay EP, Ueno M, et al. The ROCK Inhibitor eye drop accelerates corneal endothelium wound healing. Invest Ophthalmol Vis Sci. 2013 Apr 3;54(4):2493-502.
10. Koizumi N, Okumura N, Ueno M, Nakagawa et al. Rho-associated kinase inhibitor eye drop treatment as a possible medical treatment for Fuchs corneal dystrophy Cornea. 2013 Aug;32(8):1167-70.