Innovative technologies and treatment options are changing the landscape for corneal surgery and the role of corneal surgeons.
In 1997, I returned from my fellowship training at Moorfields in London and Erlangen University in Germany, having completed three years of advanced training in corneal, cataract and refractive surgery. I remember a specialist at The Sydney Eye Hospital commenting to me that he wasn’t sure why fellowship training was required for corneal transplant surgery, given that all we did was replace the windscreen of the eye. At the time I was taken aback by his description of what I considered then, and still consider, an elegant micro-surgical procedure. There was some truth, however, in what he said. A penetrating keratoplasty performed in 1997 or indeed today, is not that different from the procedure that Edvard Zirm performed in 1905.1 Obviously our instruments are better, our suture material has improved dramatically from the use of a horse or human hair and our ability to image the cornea and manage issues such as astigmatism and rejection are infinitely better than they were early last century.
That criticism could no longer be levelled against corneal transplantation. Since 1997 the improvements in corneal surgical techniques have been dramatic. Corneal surgery has been revolutionised by a rapid development of lamellar surgical techniques, both for anterior pathology
and for endothelial disease.
In many countries around the world, a deep anterior lamellar keratoplasty is now the preferred surgical procedure for keratoconus. Similarly, endothelial transplantation in its various forms and iterations is the fastest growing surgical technique for pseudophakic bullous keratopathy and Fuchs’ dystrophy.2 These three conditions make up the most common indications for corneal transplantation according to the Australian corneal graft registry.3 The results however from this valuable resource do not support superior graft survival for these newer procedures. In fact, a recent article looking at deep anterior lamellar keratoplasty results showed that the graft survival for DALK was significantly lower than penetrating keratoplasty.2 At the recent Australia and New Zealand Cornea Society meeting, I chaired a session where we discussed the shorter graft survival for endo-keratoplasty compared to penetrating keratoplasty and despite this clear difference, all corneal surgeons in the audience believed that endo-keratoplasty was the procedure of choice for all endothelial disease.
10, 15 and 20 years from now, corneal transplantation for keratoconus will no longer be the main indication for transplant surgery in Australia
This apparent disconnect of surgeon preference and evidence based medicine tells us two things. Firstly, there is significant room for improvement in our lamellar surgical techniques and secondly, that the other potential advantages of these lamellar surgeries are given more weight than graft survival.
This debate is important and on-going in Australia and New Zealand at the moment and as the surgical techniques continue to evolve, I think graft survival will improve. It is possible, however, that the issue becomes moot as these techniques fall by the way-side with the advent of new treatment options that are now becoming available. It is likely that in 10 years’ time we will be performing less corneal transplants of any variety than we are performing now. So this begs the question, “Are corneal surgeons becoming a threatened species?”
Collagen Cross-Linking
Collagen Cross-Linking has become an integral part of the management of keratoconus over the last 10 years and has revolutionised the treatment of early progressive keratoconus. The Wollensak study, commonly referred to as the Dresden protocol, utilised epithelial debridement and 30-minutes of ultra-violet exposure to improve Cross-Linking and thereby strengthen the cornea.4 Over the last decade, this technique has been widely adopted in Australia and New Zealand and indeed, one of the best prospective randomised control trials for this treatment was performed at The Royal Victorian Eye and Ear Hospital in Melbourne.5 Over the last decade, the technique and instruments have changed to some degree and it is certainly possible to deliver the same amount of UV energy in a shorter time frame and the question has also been raised as to whether or not the corneal epithelium needs to be removed.6,7 At the point of writing this article, the evidence based medicine suggests that for full effect, the 30-minute Dresden protocol is preferable. However, there is mounting evidence that a shorter duration with increased energy intensity is also effective.8,9
There are still some question marks about the side effects of Collagen Cross-Linking in the long-term and specifically the effect of Cross-Linking on wound healing if indeed a corneal transplantation is required down the track. The surgery itself does carry some risk and in my opinion and as a member of The International Delphi Panel on Keratoconus, this treatment should only be used when there is evidence of progressive disease.10
There is no question about the efficacy of crosslinking in slowing or preventing the progression of keratoconus. If all patients currently with keratoconus in Australia and New Zealand, with evidence of progressive disease, were to undergo Collagen Cross-Linking, this would mean a significant reduction in the number of corneal transplants required and performed for keratoconus. Whether the appropriate procedure is a penetrating keratoplasty or a deep anterior lamellar keratoplasty, then becomes irrelevant. I have no doubt that this will occur and that 10, 15 and 20 years from now, corneal transplantation for keratoconus will no longer be the main indication for transplant surgery in Australia.
Endo-keratoplasty
Endo-keratoplasty is a general term that encompasses all transplantation of the posterior lamellar. It includes many variations such as Descemet’s stripping automated endothelial keratoplasty (DSAEK) and more recently, Descemet’s membrane endothelial keratoplasty (DMEK), which has caught the attention of corneal surgeons around the world. Most corneal surgeons now offer as first line, either a Descemet’s stripping automated endothelial keratoplasty (DSAEK) or a Descemet’s membrane endothelial keratoplasty (DMEK) for the treatment of Fuchs’ dystrophy and pseudophakic bullous keratopathy. Both these operations can provide excellent visual results without the need for excess suturing, dry eye and the risk of leaving the eye open during the surgery.11,12 There is also a strong suggestion that DMEK, leads to less rejection.13 Of course, the trade-off is that corneal transplants do not last as long and whilst I perform both DMEK and DSAEK, I always explain to my patients the potential negatives of these procedures and the fact that it is unlikely to last as long as a full thickness transplant. In my role as Medical Director at the Eye Bank, we are currently working on modifications to the transportation of the Descemet’s membrane to improve post-operative endothelial cell counts and therefore improve longevity of the endothelial cells.
But this debate may also become redundant with the advent of new cell injection therapies and the use of ROCK inhibitors.
This revolutionary research has been pioneered by Professor Shigeru Kinoshita and Professor Noriko Koizuimi in Kyoto Japan. A ROCK inhibitor is a protein that inhibits the action of the enzyme rho-associated kinase. These enzymes are important in many signalling and metabolic pathways throughout the body and in various diseases, such as diabetes, hypertension and cancer. The pathway is involved in cell migration, cell apoptosis and cell proliferation. Professor Kinoshita’s group showed, in a landmark paper, in Investigative and Ophthalmology Visual Sciences in 2009, that a specific ROCK inhibitor led to an increase in cell proliferation and cell adhesion in endothelial cells in the monkey model, as well as decreased apoptosis.14 They subsequently went on to demonstrate in the in vivo model in both the monkey and the rabbit, that an endothelial defect could be more rapidly closed in the presence of a ROCK inhibitor.15 They have also demonstrated in a human series that in patients with localised Fuchs’ disease, the addition of a ROCK inhibitor subsequent to transcorneal freezing of damaged corneal endothelial cells, was able to cure the condition.16
A most interesting development from this pioneering research group in Kyoto, Japan, has been combining this ROCK inhibitor with cultivated endothelial cells, which are then injected into the anterior chamber. In four patients, they have utilised the ROCK inhibitor (Y-27632) and endothelial cell injection to recover corneal transparency and reduce corneal thickness.17 Whilst these are early studies, the possibility that endothelial disease might be treated by a combination of cultured injections into the anterior chamber and ROCK inhibitor eye drops, is both alluring and also potentially another nail into the coffin of the artisan corneal surgeon. It may be that in early Fuchs’ disease and early pseudophakic bullous keratopathy, all that will be required is the addition of a ROCK inhibitor eye drop. In moderate disease, this may be augmented by one or even several injections of endothelial cells and the need for corneal transplantation – whether it be a DMEK or DSAEK or penetrating keratoplasty – would no longer be required.
If this technology confirms its early promise, then once more, the need for an elite corneal trained surgeon, is specifically diminished. If I was to look into a crystal ball, I would estimate that this technology is five to ten years away, but I think that at least in some capacity, we will be using these techniques to address endothelial disease.
Corneal Refractive Surgery
There is one area of corneal surgery however, that will still require expert corneal surgeons for many years to come and that is of course, corneal refractive surgery. LASIK remains the most common corneal refractive surgery and for low and moderate levels of myopia, it is a successful procedure, despite some limitations for dry eye and hyperopia. The new SMILE procedure is also showing significant promise for moderate to high levels of myopia and there is some good evidence that this procedure is gentler on the corneal sub-epithelial plexus and may cause less dry eye.18 I have completed over 100 SMILE procedures and have found the surgery to be successful overall, but it is associated with a learning curve and does not provide as consistently rapid visual recovery as LASIK. Nevertheless, it has a clear role in the refractive surgeon’s armamentarium and is a good option for many patients providing at least theoretical benefits in terms of tectonic stability and dry eye; and is probably more predictable than LASIK for higher levels of myopia.
There is no doubt that corneal surgical skills for harvesting and dissecting the lamellar lenticule in the SMILE surgery is advantageous. I would also argue that the corneal trained surgeon is better positioned to deal with any problems that may arise in any corneal refractive surgical procedure.
Pterygium
Pterygia are a common problem in Australia and incidence increases the closer one gets to the equator.19 By and large however, this surgery is performed well by both corneal surgeons and general ophthalmologists. A major improvement in pterygium surgery has been the availability of a reliable fibrin glue, which eliminates the need for sutures. This reduces irritation and speeds visual recovery and in recent studies, has shown a reduced incidence of recurrence.20
While we may be doing less corneal transplant surgery in the future, there will still be I’m sure, plenty of pterygia that will need to be removed when they are increasing in size, causing excess irritation not relieved by topical medication or indeed causing visual loss.
Corneal Transplantation in the Developing World
Currently I am involved in running a corneal surgical skill exchange programme and eye bank programme in Mandalay, Myanmar. There are roughly only 100 corneal transplant procedures performed in the entire country of 60 million people throughout the year, yet their need is much greater than Australia on a per capita basis. There are a number of reasons for this, not the least of which is functioning, viable eye banks and surgeons with the appropriate skills. Our goal is to train these young surgeons to be able to perform the whole gamut of corneal surgical procedures, including lamellar and endo-keratoplasty surgeries. In Myanmar at least, corneal surgeons are not a threatened species, with a significant amount of corneal blindness in the country.21
In June, I will also be part of a guest faculty in a corneal surgical training programme at the LV Prasad Hospital, India. India has an extremely high incidence of corneal blindness and a very high incidence of keratoconus. What they are lacking is corneal surgeons. The fact is that corneal surgeons are remunerated very poorly in India and anyone who has managed a corneal transplant over a long period of time, knows that it requires dedication, commitment and that the relationship between surgeon and patient is life-long.
So my message to any corneal surgeon in Australia and New Zealand who feels threatened by advances in technology is twofold… You won’t be doing as many transplants in 10 years as you are doing now, however, there will certainly be plenty of work to do in developing countries and a need to train and teach there for many years to come.
Professor Gerard Sutton is an internationally recognised ophthalmic surgeon who has performed over 15,000 vision correction procedures. He specialises in laser eye surgery, laser cataract surgery and corneal transplantations and has a special interest in the treatment of keratoconus. Prof. Sutton is the inaugural Professor of Corneal and Refractive Surgery at the Save Sight Institute, University of Sydney and is the Medical Director of the Lions NSW Eye Bank. He practises at Vision Eye Institute.
References:
1. Coster DJ. History of corneal transplantation in Australia. Clin Experiment Ophthalmol. 2014 Aug 11. doi: 10.1111/ceo.12408. [Epub ahead of print]
2. Coster DJ, Lowe MT, Keane MC, Williams KA. Australian Corneal Graft Registry Contributors. A comparison of lamellar and penetrating keratoplasty outcomes: a registry study. Ophthalmology. 2014 May;121(5):979-87. doi: 10.1016/j.ophtha.2013.12.017. Epub 2014 Feb 1.
3. Williams KA, Lowe MT, Keane MC, Jones VJ, Loh RSK, Coster DJ. The Australian Corneal Graft Registry 2012 Report. URL: http://hdl.handle.net/2328/25859 (Date: 2012-03-05). Accessed 15th April 2015.
4. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003 May;135(5):620-7.
5. Wittig-Silva C, Chan E, Islam FM, Wu T, Whiting M, Snibson GR. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. Ophthalmology. 2014 Apr;121(4):812-21.
6. Tomita M, Mita M, Huseynova T. Accelerated versus conventional corneal collagen crosslinking. J Cataract Refract Surg. 2014 Jun;40(6):1013-20. doi: 10.1016/j.jcrs.2013.12.012.
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8. Elbaz U, Shen C, Lichtinger A, Zauberman NA, Goldich Y, Chan CC, Slomovic AR, Rootman DS. Accelerated (9-mW/cm2) corneal collagen crosslinking for keratoconus-A 1-year follow-up. Cornea. 2014 Aug;33(8):769-73.
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11. Nanavaty MA, Wang X, Shortt AJ. Endothelial keratoplasty versus penetrating keratoplasty for Fuchs endothelial dystrophy. Cochrane Database Syst Rev. 2014 Feb 14;2:CD008420.
12. Ple-Plakon PA, Shtein RM. Trends in corneal transplantation: indications and techniques. Curr Opin Ophthalmol. 2014 Jul;25(4):300-5.
13. Price FW Jr, Price MO. Evolution of endothelial keratoplasty. Cornea. 2013 Nov;32 Suppl 1:S28-32.
14. Okumura N, Ueno M, Koizumi N, Sakamoto Y, 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.
15. Okumura N, Koizumi N, Ueno M, Sakamoto Y, Takahashi H, Hirata K, Torii R, Hamuro J, Kinoshita S. Enhancement of corneal endothelium wound healing by Rho-associated kinase (ROCK) inhibitor eye drops. Br J Ophthalmol. 2011 Jul;95(7):1006-9.
16. Koizumi N, Okumura N, Ueno M, Nakagawa H, Hamuro J, Kinoshita S. Rho-associated kinase
inhibitor eye drop treatment as a possible medical treatment for Fuchs corneal dystrophy. Cornea. 2013 Aug;32(8):1167-70.
17. Koizumi N, Okumura N, Ueno M, Kinoshita S. New therapeutic modality for corneal endothelial disease using Rho-associated kinase inhibitor eye drops. Cornea. 2014 Nov;33 Suppl 11:S25-31.
18. Denoyer A, Landman E, Trinh L, Faure JF, Auclin F, Baudouin C. Dry Eye Disease after Refractive Surgery: Comparative Outcomes of Small Incision Lenticule Extraction versus LASIK. Ophthalmology. 2015 Apr;122(4):669-76.
19. Mackenzie FD, Hirst LW, Battistutta D, Green A. Risk analysis in the development of pterygia.Ophthalmology. 1992 Jul;99(7):1056-61.
20. Cagatay HH, Gokce G, Ekinci M, Koban Y, Daraman O, Ceylan E. Long-term comparison of fibrin tissue glue and vicryl suture in conjunctival autografting for pterygium surgery. Postgrad Med. 2014 Jan;126(1):97-103.
21. Nemet AY, Nemet P, Cohn G, Sutton G, Sutton G, Rawson R. Causes of blindness in rural Myanmar (Burma): Mount Popa Taung-Kalat Blindness Prevention Project. Clin Ophthalmol. 2009;3:413-21.
