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6 Gulani Refractive Descemet’s Endothelial Keratoplasty (REFDEK) Classification

6 Gulani Refractive Descemet’s Endothelial Keratoplasty (REFDEK) Classification

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13



Targeting Emmetropia in Endothelial Keratoplasty



213



Fig. 13.7 Poorly done DSAEK or failing endothelial keratoplasty can be rejuvenated and

enhanced using REFDEK principles

Fig. 13.8 Endothelial

keratoplasty (REFDEK)

in a case of radial

keratotomy



13.6.3



Postoperative



A. Excimer Laser ASA (advanced surface ablation) can be used to correct residual

refractive errors to emmetropic outcomes (Fig. 13.9).

B. Lens implant-based optical manipulations can be undertaken, i.e., piggyback

lens, toric lens rotation and only if needed, lens exchange surgery too as we

would in any patient expectant of refractive outcomes (Fig. 13.10).

C. Miscellaneous: Given proper indications, I do not see a contraindication to even

using collagen cross-linking in cases of endothelial keratoplasty in RK cases

once refractively stable or touch of procedures like astigmatic keratotomy, Femto

laser astigmatic keratotomy, conductive keratoplasty, etc.

In summary then, excited as we are about the surgical evolution of endothelial

keratoplasty from DSEK to DMEK and PDEK, let us also raise the bar on ourselves

and deliver vision at the highest level we can through this exciting procedure once

again not only in restoring anatomic function but also vision outcomes.

With technologies today ranging from new-generation excimer lasers, femtosecond technology, lens implants with individualized optics, refractively fine tuning procedures, and permanizing techniques like collagen cross-linking, we can

truly live up to ever-enchanting properties of the cornea which not only provides



214



A.C. Gulani



Fig. 13.9 The patient in

Fig. 13.4 at 6 months

underwent laser vision

surgery to 20/20

uncorrected vision



Fig. 13.10 Toric lens implant with endothelial keratoplasty planned to emmetropic outcome



transparency to see the outside world but also has the optical power to focus our

vision [14–16].

May I take this opportunity then to reiterate my respects to our cornea by calling

it our “Vision rehabilitative platform!”



13



Targeting Emmetropia in Endothelial Keratoplasty



13.7

13.7.1



215



My Personal Techniques

Minimal DSAEK Surgery: Gulani Key Hole Transplant

(REFDEK)



(i) Specifics: topical anesthesia, sutureless superior incision, single instrument

surgery.

(ii) Advantages:

• Since most of the referred cases of PBK have had cataract surgery with a

temporal incision, my preferred approach is a superior limbal incision which

allows me to operate in an untouched area with good self-sealing incision

architecture. This area also is cosmetically under the upper lid and therefore

next day postop these patients look like they have had no surgery.

• Single instrument (Gulani scorer and peeler) allows for less tissue manipulation and elegant working in a closed system, double paracentesis arena (until

the main incision is entered).

• Topical anesthesia allows for faster recovery and ocular medication toward

an encouraging outcome.

• Sealant option if needed (Fig 13.11).



Fig. 13.11 ReSure sealant was used in this case for excellent refractive and anatomic outcome



216



A.C. Gulani



References

1. Facts about the cornea and corneal diseases. National Eye Institute. National Institutes of

Health, 1 May 2013. Web. 28 Oct 2014. http://www.nei.nih.gov/health/cornealdisease/.

2. Cassin B, Solomon S. Dictionary of eye terminology. Gainesville: Triad Publishing Company;

1990.

3. Sayegh F. The correlation of corneal refractive power, axial length, and the refractive power of

the emmetropizing intraocular lens in cataractous eyes. Ger J Ophthalmol. 1996;5(6):328–31.

PubMed. Web. 28 Oct 2014. http://www.ncbi.nlm.nih.gov/pubmed/9479513.

4. MerindanoEncina MD, Potau JM, Ruano D, Costa J, Canals M. A comparative study of

Bowman's layer in some mammals relationships with other constituent corneal structures. Eur

J Anat. 2002;6(3):133–40.

5. Corneal conditions. Cornea Research Foundation of America. Web. 5 Oct 2014. http://www.

cornea.org/index.php/research/corneal_conditions.

6. Stodola E. Cornea surgeons compare thin DSAEK and DMEK as options for endothelial keratoplasty procedures. EyeWorld. 1 Jan 2013. Web. 28 Oct 2014. http://www.

eyeworld.org/article-cornea-surgeons-compare-thin-dsaek-and-dmek-as-options-forendothelial-keratoplasty-procedures.

7. Fernandez M, Natalie A. How to perform Descemet’s stripping automated endothelial keratoplasty. American Academy of Ophthalmology. EyeNet Magazine, 1 Jan 2007. Web. 28 Oct

2014. http://www.aao.org/publications/eyenet/200701/pearls.cfm.

8. Shaw J. DMEK: A new contender for corneal transplantation. American Academy of

Ophthalmology. EyeNet Magazine, 1 Sept 2012. Web. 28 Oct 2014. http://www.aao.org/publications/eyenet/201209/cornea.cfm.

9. Agarwal A. Pre Descemet’s Endothelial Keratoplasty (PDEK): A novel method of endothelial transplantation. EyeWorld. 1 Jan 2014. Web. 28 Oct 2014. http://www.eyeworld.org/

article-pre-descemet-s-endothelial-keratoplasty--pdek----a-novel-method-of-endothelial-transplantation.

10. Agarwal A, Priya N. PDEK: a revolution in corneal transplantation. Ophthalmology

Management. 1 Mar 2014. Web. 28 Oct 2014. http://www.ophthalmologymanagement.com/

articleviewer.aspx?articleID=110224.

11. Gulani AC. Tips, insights, and techniques from other surgeons. In: Price F, editor. Textbook –

DSEK what you need to know about endothelial keratoplasty, vol. 9. Thorofare: SLACK Inc;

2009. p. 113–5.

12. Gulani AC. Key hole corneal transplant. Surgical techniques in ophthalmology corneal surgery. JP Publ. 2009;25:154–6.

13. Gulani AC. Corneoplastique™: art of vision surgery. Indian J Ophthalmol. 2014;62:3–11.

14. Gulani AC. Evaluating the impact of femto laser-assisted capsulotomy. Cataract Refract Surg

Today Eur. 2014;9(2):36–50.

15. Gulani AC. Decoding corneal scars: straight to 20/20. Ophthalmol Times. 2014;39(4):6–12.

16. Gulani AC. Corneoplastique. Tech Ophthalmology. 2007;5(1):11–20.



Chapter 14



Rhokinase Inhibitors for Endothelial

Decompensation

Dhivya Ashok Kumar



Contents

14.1 Introduction

14.2 Endothelium

14.3 Rhokinase Enzyme and Its Role

14.4 In Vitro Studies with Monoclonal Endothelial Cells (MCECs)

14.5 In Vivo Rhokinase Inhibitors

14.6 Human Trials

14.7 Conclusion

References



14.1



217

218

218

219

219

220

220

221



Introduction



Cornea is a unique structure with varied physiological mechanism working for its

transparency and integrity. Orientation of collagen, arrangements of keratocytes,

fluid transport mechanism, endothelial cell function and proteoglycan proportions

are some of the factors which contribute to its physical nature. Conditions which

hinder the above normal systematic functions are known to affect corneal transparency. Corneal endothelial cell is one vital structure which is highly efficient in preserving the vitality of the corneal layers.



D.A. Kumar, MD, FICO

Consultant and Head R&D, Dr. Agarwal’s Refractive and Cornea Foundation,

Dr. Agarwal’s Eye Hospital and Eye Research Centre, 19, Cathedral Road,

Chennai, TN 600086, India

e-mail: susruta2002@gmail.com

© Springer India 2016

S. Jacob (ed.), Mastering Endothelial Keratoplasty,

DOI 10.1007/978-81-322-2821-9_14



217



218



14.2



D.A. Kumar



Endothelium



Corneal endothelium is a 5-μm thick single monolayer of cell spread along the posterior most part of the cornea. It has active pumps for ionic and fluid transport across

it. Conditions like trauma, congenital cell damage (Fuchs’ endothelial dystrophy or

posterior polymorphous dystrophy) and post-surgery (cataract or vitreoretinal) can

affect its routine function. Abnormal cell morphology in normal cell count or low

pre-operative cell count or endothelial damage intra-operatively can cause this. It is

known that endothelial cell has less potential to regenerate due to the following

reasons: (1) cell-to-cell contact inhibition, (2) G1 phase arrest, (3) less response to

microenvironment stimulators, and (4) TGF-B2 suppression of S phase [1]. Though

there are varied surgical treatment options like penetrating and endothelial keratoplasty in advance cases of corneal endothelial decompensation, only few medical

management options have been tried in early cases.



14.3



Rhokinase Enzyme and Its Role



The Rho/ROCK pathway is known to be involved in regulating the cytoskeleton,

cell migration, cell apoptosis, and cell proliferation. ROCK inhibitor Y27632 specifically blocks ROCK1 (P160ROCK). Chemically, it is trans-4-(1-aminoethyl)-N(4-pyridyl) cyclohexane carboxamide dihydrochloride. It has shown to have some

promising effects in corneal endothelial decompensation [2–4]. ROCK regulates the

formation of actin stress fibres assembly and cell contraction (Fig. 14.1). In addition



Rhokinase



Myosin light

chain

phosphatase



Contraction



ERM family



P27

ERK1/2



Cell

adhesion &

migration



Fig 14.1 Schematic picture showing the functions of rhokinase pathway



Cell

propagation



14



Rhokinase Inhibitors for Endothelial Decompensation



219



to the primary function in cytoskeleton remodelling and migration, Rho signalling

pathway has been shown to be involved in the regulation of other biological processes like gene transcription, G1 cell cycle progression and apoptosis [5]. It has

been demonstrated that ROCK inhibitors use both cyclin D and p27 through PI

3-kinase signalling to promote corneal endothelial cell proliferation [6]. The ROCK

pathway is involved in regulating various cell functions such as migration, apoptosis, differentiation, and proliferation which are cell-type dependent [7–9]. Because

the ROCK pathway is involved in a variety of diseases, ROCK inhibitors have been

developed as therapeutic drugs for endothelial dysfunction [10].



14.4



In Vitro Studies with Monoclonal Endothelial Cells

(MCECs)



Okumura et al. immunostained MCECs for the cell cycle population marker Ki67

[11]. MCECs cultured with Y-27632 showed the presence of a larger number of

Ki67-positive cells compared with the controls. Quantitative flow cytometric analysis revealed an increased number of Ki67-positive cells in MCECs cultured with

Y-27632. Additionally, BrdU-labelling assays were conducted to confirm the effect

of Y- 27632 on cell proliferation. They revealed a significantly greater number of

BrdU-positive MCECs among the Y-27632-treated cells compared with the control

cells. This demonstrated that Y-27632 plays a central role in the proliferation of

MCECs.

In the same study, MCECs were cultured to confluence over a 14-day period and

were scraped with a plastic pipette tip to create linear defect sites, and the culture

was then continued for a further 24 h in fresh medium with or without 10 mM

Y-27632. The mean wound distance was noted to be significantly shorter in the

Y-27632 group than in the control group [11]. These findings suggested that Y-27632

promoted wound healing in the in vitro model. A study by Pipparelli et al. showed

that the selective ROCK inhibitor Y-27632 has no effect on human corneal endothelial cells proliferative capacities, but alters cellular behaviours [10]. It induces

changes in cell shape, increases cell adhesion, and enhances wound healing ex vivo

and in vitro. Its absence of toxicity, as demonstrated herein, is relevant for its use in

human therapy [10].



14.5



In Vivo Rhokinase Inhibitors



In an in vivo animal experiment, a corneal endothelial wound was initially made,

then 10 mM Y-27632 was applied topically six times daily in the form of eye drops

over a 2-day period in rabbits [11]. Slit-lamp microscopic examination showed that

corneal transparency and corneal thickness recovered faster in the Y-27632 group

compared to the control group. Ultrasound pachymetry revealed that the corneal

thickness was significantly thinner in the Y-27632 group compared to the control



220



D.A. Kumar



group after 48 h of treatment. Rabbits were then euthanized, and the wound area of

the corneal endothelium was evaluated by Alizarin red staining following enucleation after 48 h. The mean wound area of the Y-27632 group was significantly

smaller than that of the control group. These results demonstrated that the topical

administration of Y-27632 eye drops enhances endothelial wound healing [11].

In an animal model, Okumura compared rhokinase inhibitors with endothelial

cell injection in vivo in rabbit eyes [12]. Rabbit eyes were injected with cultivated

rabbit corneal epithelial cells (RCECs) with the selective ROCK inhibitor Y-27632

and those cultivated RCECs without Y-27632. A control corneal endothelial dysfunction model was also kept. The eyes were assessed after 48 h. Rabbit eyes

injected with cultivated RCECs combined with Y-27632 recovered complete transparency of the cornea. In contrast, eyes injected with cultivated RCECs without

Y-27632 and control eyes exhibited a hazy cornea with severe oedema. Injection of

cultured MCECs with a ROCK inhibitor regenerated healthy corneal endothelium

and recovered corneal transparency in the monkey model, similar to the findings in

the rabbit model [12]. The first human clinical trial has now been initiated.



14.6



Human Trials



Koizumi et al. reported the effect of rhokinase inhibitor in human eye in a patient

with Fuchs’ corneal dystrophy [13]. The patient was treated by a corneal endothelial

denudation in the prepupillary region followed by the topical administration of a

selective ROCK inhibitor, Y-27632, as eye drops for 1 week (50 mL of 10 mM

ROCK inhibitor, Y-27632, was applied topically as eye drops, repeated six times

daily for 7 days) and followed up for 24 months. Corneal clarity was noted to

improve after 2 weeks of treatment and endothelial function was observed to sustain

for 24 months. In a trial by Okumura et al., the effect of Y-27632 eye drops after

transcorneal freezing was evaluated in eight corneal endothelial dysfunction

patients: four central corneal oedema patients and four diffuse corneal oedema

patients [14]. The clinical study showed that Y-27632 eye drops effectively improved

corneal oedema of corneal endothelial dysfunction patients with central oedema.



14.7



Conclusion



Although corneal transplantations provide considerable clinical benefits, graft

rejection, primary graft failure, and the shortage of donor corneas are problems that

still need to be overcome. Rhokinase inhibitors are in the early stage of its functional assessment in human eyes, and reports exhibit that ROCK inhibitor converts

corneal endothelial cells into a phenotype capable of regenerating in vivo endothelial tissue [15]. Further investigations are necessary; the topical instillation of the

ROCK inhibitor might be a clinically applicable and a less invasive therapeutic

modality for the treatment of corneal endothelial dysfunction in future.



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