Perioperative Use of Rho-Kinase Inhibitors has Beneficial Effect on Corneal Endothelium after Phacoemulsification.

PURPOSE: Does perioperative use of Rho-Kinase (ROCK) inhibitors have beneficial effect on corneal endothelial cells after phacoemulsification?
SETTING: This study was conducted at King Abdulaziz University Hospital in Riyadh.
DESIGN: This was a prospective study assessing the effect of ROCK inhibitors on corneal endothelium after phacoemulsification.
METHODOLOGY: Three patients have used ROCK inhibitor 1 day before and 1 week after phacoemulsification surgery, and specular microscopy and Pentacam were done preoperatively and 3 months postoperatively.
RESULTS: Endothelial cell density decreased to 11.3%, 9.45%, and 4.09% in eyes with ROCK inhibitors and 23.9% in one eye without ROCK inhibitor.
CONCLUSION: Perioperative ROCK inhibitor use has a possible protective effect on corneal endothelium. Copyright:

Introduction

Corneal endothelium is known as a single layer of cells which are normally not regenerated once damaged. Humans are born with 6000 cells/mm2 endothelial cells.[1] These cells decrease at an average of 0.6% each year.[2] Endothelial density of <500 cells/mm2 imposes high risk of corneal decompensation and consecutively hazy vision.[3] The only approved solution for corneal decompensation is corneal transplantation.[4] Although corneal endothelial transplantation has become less invasive with the evolution of Descemet stripping endothelial keratoplasty and Descemet membrane endothelial keratoplasty, surgical intervention still has some issues such as technical difficulty, risk of graft rejection, and intraocular infection.[5]

Tissue engineering therapy through Rho-kinase (ROCK) signaling pathway inhibition has demonstrated diverse therapeutic potential in vascular diseases, cancer, neuronal degenerative disease, asthma, and glaucoma through changing cell behavior.[6789] Topical preparation of ROCK inhibitor Ripasudil hydrochloride hydrate (Glanatec® ophthalmic solution 0.4%; referred to as ripasudil) was found to be useful as glaucoma treatment by stimulating drainage of aqueous humor through direct action on trabecular meshwork[10] with only minor adverse events reported including conjunctival hyperemia, photophobia, other eye discomfort, and asthma.[911] Further studies demonstrated another promising ophthalmic use after showing that ROCK inhibitors can promote corneal endothelial cell proliferation[12] and healing.[13] The proposed mechanism for ROCK inhibitors action on corneal endothelium is mediated through phosphatidylinositol 3-kinase signaling that subsequently regulates two proteins of the G1 phase of the cell cycle.[14] Currently, no studies demonstrate the proper dosage of ROCK inhibitors in various corneal diseases, nor any contraindications for their ophthalmic usage.[5] Ripasudil has demonstrated its therapeutic potential targeting corneal endothelium in the treatment of acute corneal endothelial damage following eye surgeries.[15] Further studies suggested that ROCK inhibitors might be used to prevent postoperative acute corneal edema due to corneal endothelial dysfunction.[16]

This study was done to detect the effects of perioperative use of ripasudil on healthy corneal endothelium in patients who undergo uncomplicated phacoemulsification cataract surgery.

Methodology

After ethical approval was granted from the department committee, three male patients of 65, 62, and 67 years of age were planned for phacoemulsification surgery. Patients 1 and 3 were hypertensive on medications. Preoperative evaluation included detailed history, bestcorrected visual acuity, slitlamp examination, fundus examination, Goldmann applanation tonometry and specular microscopy. All patients who were chosen had grade 3 nuclear cataract using Pentacam Nucleus Staging Software which depends on Pentacam's Scheimpflug camera with a grade from 0 to 5. Informed consent was taken from all the participants with all benefits and risks being explained to each patient of the procedure as well as the use of ROCK inhibitor. 1 mM Ripasudil (Glanatec® ophthalmic solution 0.4%) was instilled to the study eye three times a day preoperatively and then the same dosage was used postoperatively for 1 week.

The change in corneal endothelial cell density (ECD) was compared with the normal population using specular microscopy (using Specular Microscope, SP 3000P, Topcon), with the IMAGEnet imaging system (Topcon Medical Systems, Inc., Oakland, USA) done preoperatively and 3 months after surgery in all three patients. Measurements of central corneal ECD (cells/mm2), coefficient of variation in corneal endothelial cells (CV), percentage of hexagonal cells, and central corneal thickness (CCT) were taken.

All patients were operated by a single surgeon using a standard endocapsular, stop and chop technique using the same machine (Infiniti vision system; Alcon Laboratories; Inc., Fort Worth, TX, USA).

A 2.2 mm superotemporal self-sealing clear corneal incision was made just in front of the vascular arcades of the corneoscleral limbus using a calibrated 2.2 mm keratome. Ocular viscoelastic device (Sodium Hyaluronate; Provisc) was injected into the anterior chamber. A paracentesis incision of 1 mm was made 60° apart with a 20-gauge microvitreoretinal blade. Iris hooks were used for the second and the right eye of third patients for mechanical dilation because of age-related pupil suboptimal dilation. After the capsulorrhexis, hydrodissection followed by nucleus rotation, nucleus removal was done by a single method, that is, stop and chop technique. After emulsification of nuclear fragments, irrigation aspiration of residual cortical matter was done. A foldable intraocular lens was implanted inside the capsular bag. After this, the removal of the viscoelastic material was done, and finally, the incision was hydrated using a 30-gauge cannula. One 10-0 nylon suture was applied to the main wound of the second patient only, while the main wound on other patient was sealed with stromal hydration. The eye was bandaged which was opened next morning. Intraoperative Cumulative Dissipated Energy (CDE) was calculated as mean tortional power × 0.4 × phacoemulsification time as the only phacoemulsification power used was the tortional.

Results

Four eyes of three patients were included. Right eyes were operated in patients 1 and 2, whereas both eyes were operated in patient 3. In the first patient, preoperative visual acuity of the right eye was 20/60. Intraoperative CDE used was 45 and there was 11.3% loss in ECD, 2.9% change in hexagonality, and 0.91% increase in CCT. Postoperative visual acuity was 20/20 3 months postoperatively. In the second patient, preoperative visual acuity of the right eye was 20/80. CDE used was 12 and had 9.45% ECD loss, 4.05% change in hexagonality, and 0.68% increase in CCT. Visual acuity was improved to 20/25 3 months postoperatively. In the third patient, whose preoperative visual acuities were 20/60 and 20/50, only the right eye was instilled with ROCK. CDE used was 23 in both eyes. The ECD was reduced by 4.09% in the right eye while reduced only by 23.9% in the left eye. CCT increased 1.59% in both eyes. Three months postoperatively, visual acuity was improved to 20/20 in both eyes. Table 1 shows CED, CV, and hexagonality preoperatively and 3 months postoperatively in the 4 eyes of 3 patients, with the calculation of intraoperative CDE and percentages of change in CED and CCT.

Table 1

Corneal endothelial cell density, CV, and hexagonality preoperatively and 3 months postoperatively in the 4 eyes of 3 patients, with the calculation of intraoperative Cumulative Dissipated Energy and percentages of change in corneal endothelial cell density and central corneal thickness

	Preoperative	CDE	3 months postoperative	Change in endothelium
1st patient	CED 2893	45	CD 2566	11.3%
	CV 32%		CV 37%
	HEX 68%		HEX 66%
	CT 546		CT 551	0.91%
2nd patient	CED 2392	12	CD 2166	9.45%
	CV 25%		CV 28%
	HEX 74%		HEX 71%
	CT 587		CT 591	0.68%
3rd patient OD Using rho (right)	CED 2663	23	CD 2554	4.09%
	CV 46%		CV 49%
	HEX 54%		HEX 51%
	CT 563		CT 574	1.59%
3rd patient Without rho (left)	CED 2619	23	CD 1992	23.9%
	CV 25%		CV 33%
	HEX 77%		HEX 58%
	CT 567		CT 576	1.59%

CED: Corneal endothelial cell density, CDE: Cumulative dissipated energy, CD: Cell density, HEX: Hexagonality, CV: Coefficient of variation in corneal endothelial cells, CT: Computed tomography

Discussion

The evolution of ROCK inhibitors ophthalmic uses has prompted researchers to prove their beneficial effects on corneal endothelium, especially after damage caused by phacoemulsification surgery.[5] Some researchers propose that ROCK inhibitors promote proliferation of corneal endothelial cells.[17] However, the specific mechanism by which ROCK inhibitors affect corneal endothelium is not clear. In this study, loss of CED ranged from 4.09% to 11.3% when ROCK inhibitor was applied, which is less than what was found in the normal population by Xing Du et al.[18](12.4%) and Walkow et al.[19](11.9%). Changes in CCT after the use of ROCK inhibitors were 0.91%, 0.68%, and 1.59% when ROCK inhibitors were used, which are comparable to changes detected by 0.6% found in the normal population by Salvi et al.[20] and less than changes detected by Das et al. (1.7%)[21] and Vasavada et al. (4.3%).[22] For the patient who had bilateral phacoemulsification surgery with the use of ROCK inhibitors in the right eye only (patient 3), loss of CED in the left eye was higher after phacoemulsification (23.9%) despite the use of the same intraoperative CDE. Changes in CV and hexagonality were more in the left eye for which ROCK inhibitor was not applied, although there was similar changes in CCT in both eyes (1.59%). The minimal changes in CED and CCT in comparison to normal population indicate that ROCK inhibitors have beneficial effect on corneal endothelial cells when administered topically perioperatively. The authors can argue that the use of iris hooks along with corneal suturing in patient 2 and only iris hooks in the right eye of patient 3 might have compromised corneal endothelium even further without the use of ROCK inhibitors. The limited effect of ROCK inhibitors on postoperative visual acuity in our patients, might limit their clinical usefulness to cases with expected significant corneal endothelial compromise after phacoemulsification, such as Fuch's Corneal Endothelial Dystrophy, as well as patients with dense cataracts. The use of ROCK inhibitors might prevent postoperative significant visual deterioration.

Limitations of the study include small number of patients and further studies are needed to know the ideal dosage regimen for best action on corneal endothelium and to know the exact mechanism by which ROCK inhibitors act on corneal endothelium to promote its healing after phacoemulsification.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.