The Magic in Layered Corneal Transplantation

The cornea is the smallest transplanted body tissue; anything smaller is cellular. Despite its tiny size, modern transplant surgery has evolved to such a degree that all the separate layers of the cornea can now be selectively replaced, and layered transplantation surgery has advanced rapidly to become the gold standard in corneal transplantation.

The cornea is an optical structure lined on one side by skin and on the other side by cells. This makes it a fluid barrier (separating air from aqueous), a physical barrier, a support structure and a lens, yet it is just 0.5mm thick. The reason it can do all these things is because of its mixed embryological origins.

Layered transplantation can be broken down according to the major functional layers of the cornea:

1. Skin lining (epithelium)

2. Physical structure (stroma)

3. Fluid barrier (endothelial cells)

Such flexibility with corneal transplantation has been a revolution…
because of what it means to patient recovery and reduction of risk

Of these layered transplants, epithelial and stromal transplantation have been around for decades. Layered stromal transplantation was performed well before full thickness transplantation and has commonly been taught as a reconstructive procedure rather than a sight restorative procedure. Reconstructive stromal transplantation – also called ’tectonic‘ grafting – is used to repair holes in the eye and prevent its loss. So if layered transplantation has been around for so long, what makes it new, and what has advanced to make it a routine procedure for sight restoration?

To understand that, we will first consider the most recent revolution in lamellar transplantation, the endothelial transplant (ET), also known as endothelial keratoplasty. The endothelial transplant has made lamellar transplantation popular because it has revolutionised the management of Fuchs corneal dystrophy, a heritable premature loss of the endothelial cell barrier of the cornea, leading to vision loss due to aberrations within Descemet’s membrane and corneal swelling.

With change comes confusion, and some of that confusion is semantics. The linguistics used confuses almost everyone and for the patient already struggling to understand the nature of their condition, the treatment sounds worse! Acronyms have arisen at each stage of advance, furthering the confusion and in some cases, stagnating progress. To make it easier to understand, think in terms of what is being replaced, rather than a meaningless acronym.

If we stick to fundamentals:

• If the skin of the eye is damaged, replace it (epithelial transplant)

• If the physical structure of the cornea limits vision, replace it (stromal transplant)

• If the fluid barrier of the cornea limits vision, replace it (endothelial transplant).

Of these three types of transplants, epithelial transplantation is still relatively primitive, while stromal and endothelial transplantation have advanced significantly. So, what has happened to advance these two surgeries? Despite the fact that ophthalmic surgery just loves pushing new technology, it may be surprising to consider the most advanced microsurgical transplantation is not due to technology but technique, and that this surgery is performed manually. Repeated attempts have been made to use current laser technology, and these attempts have failed: the tools have no current place in advanced lamellar transplantation surgery. We don’t need laser, quantum or nano tools… for advanced results, we use older technology combined with improved techniques.

Let’s start with the most recent advance – the endothelial transplant.

ENDOTHELIAL TRANSPLANTATION

This is by far the most popular layered transplant today, due to its simplicity, and wide uptake in the USA, increasing its recognition and use. Endothelial transplantation is indicated for any disease that compromises integrity of the endothelial or Descemet’s layer to the point that vision is degraded. The endothelial transplant has led to widespread general acceptance of layered corneal transplantation today.

Development of Endothelial Transplantation

The earlier techniques were crude: deep lamellar endothelial keratoplasty (DLEK) transplanted the posterior cornea including stroma, Descemet’s and endothelium. Tissue dissection of the donor tissue was clumsy and cumbersome, and then the same had to be performed on the recipient eye, requiring large incisions to remove the same posterior stroma, Descemet’s membrane and endothelium. Surgery took a long time, and vision improvement was suboptimal. Then came the realisation that such extensive dissection of the patient’s cornea was not needed, as Descemet’s membrane could be split along its banded and nonbanded layers. Stripping Descemet’s reduced the amount of surgery that had to be done on the patient, and the operation immediately became minimally invasive. Acceptance grew because stripping Descemet’s wasn’t much more difficult than tearing open a packet of crisps. The phrase “Descemet’s stripping…” became the prefix for subsequent endothelial keratoplasty surgeries.

Now, the problem was preparing the donor tissue and putting it into the recipient eye, beginning with the same manual approach used to harvest donor tissue with PLK. The acronym ‘DSEK’ appeared, meaning Descemet’s Stripping Endothelial Keratoplasty, whereby a thick layer of stroma containing Descemet’s membrane and endothelium was obtained, and crudely inserted into a patient eye. Techniques to insert literally required folding the tissue onto itself like a taco – forming a bifold and trifold – however, this was quite damaging to endothelium, and the failure rate was significant. Eventually, the world settled on sliding or pulling the tissue into the eye with forceps, which worked for a time. The procedure was promoted, and the meaningless acronym has stuck.

The thick, irregular, manually prepared donor DSEK tissue caused optical issues that reduced the best visual outcome. However, one possible solution had already been invented: the LASIK microkeratome was already in use to make layers in patient corneas, so it was put to work to prepare the donor tissue. This procedure didn’t just create a smoother surface – it was fast, surgeons were familiar with it, and often already owned the technology. ‘DSAEK’ had arrived, or Descemet’s Stripping Automated Endothelial Keratoplasty, and popularity of the technique in northern America exploded.

But there was a problem: vision recovery was relatively slow, and most people did not reach their best visual potential. This was in part due to the change in optics of the cornea that resulted from thickening the cornea significantly, to as much as 750 microns or more. The normal corneal evolutionary anatomy had been changed.

The revolution occurred with the arrival of ‘DMEK’ – Descemet’s Membrane Endothelial Keratoplasty. Note that the word ‘stripping’ has been removed, and this acronym more appropriately describes the technique of transplanting only endothelial cells on their supporting membrane, Descemet’s membrane. This technique has the potential to deliver perfect vision, is less damage to donor endothelial tissue, and a rapid return of vision.

The donor tissue is prepared manually by peeling the Descemet’s membrane from the stroma along the pre-Descemet’s plane which does not require expensive equipment but is technically challenging. Once peeled, the tissue rolls up into a scroll, which makes inserting it into the eye difficult. Before insertion, the recipient cornea is prepared by splitting Descemet’s and removing the inner portion containing guttatae. Many techniques are described, and the common one today is injecting it into the eye, and then, with application of pressure to the dome of the cornea, unfolding it in the anterior chamber. The trick is to make sure it unfolds correct side up, otherwise it won’t stick. A bubble of air supports this sliver of tissue against the back surface of the cornea, waiting for the cells to start pumping and stick the tissue into place. Optically, the DMEK is far superior, returning the host cornea to almost perfect evolutionary anatomy.

DMEK ADVANTAGES

DMEK allows many patients to achieve their visual potential, with nearly 50 per cent achieving 6:6 vision.¹ Best results occur in phakic eyes, probably because of the correction of spherical aberration by the crystalline lens. Vision returns rapidly over weeks, and the minimally invasive surgery is performed through a keyhole cataract surgery wound. Because there is little tissue trauma, there is less damage to the eye, and less need for drops postoperatively, reducing complications like steroid induced glaucoma and cataract. By far the greatest advantage is the stunningly low rate of endothelial rejection – less than 1 per cent² – which came as a surprise because most full thickness transplant rejection is attributed to endothelial rejection. Although counter to the teaching of the day, it turns out the stroma is much more antigenic than the endothelium.

Increasing DMEK Life

After any corneal transplant, there is an initial immediate reduction in endothelial cells. This is thought to be due to surgery induced trauma to the tissue. This initial cell loss slows over six months, but there is a much slower progressive endothelial cell loss over time, and this can lead to primary graft failure of the DMEK. As primary failure is the most common cause of DMEK failure, a method to prolong the life of the transplant is to transplant more cells, which means a bigger transplant. Size matters. My preference for transplantation is to use the largest transplant possible, and not to directly handle the tissue. Fortunately, mathematics is on our side as the relationship of cell number to transplant size is exponential not linear. The area of the tissue increases with the square of the radius, so if we assume a cell count of 2000/mm², then consider the following:

A 1.5mm increase in diameter delivers more than 40 per cent more cells! I have also found that long term low dose steroid usage after transplantation reduces the rate of endothelial cell loss, increasing DMEK life.

DMEK Difficulties

Unfortunately, there is no Nirvana: such a revolution doesn’t make surgery ‘easy’ or eliminate adverse outcomes. DMEK brings with it very unusual problems, mostly related to getting the donor cells to stick to the host cornea. Sometimes, they just don’t adhere, and sometimes the tissue rolls into a scroll. Often, more air is required to attach the cells, and this means injecting air into the eye a few days after surgery to keep the donor tissue in place. Fortunately, exchanging a DMEK is minimally invasive.

There are situations where the DMEK technique becomes more difficult. These include:

1. Advanced glaucomatous eyes

2. Vitrectomy/retinal detachment eyes

3. Loss of the iris from trauma or congenital aniridial

4. Aphakia

5. Previous full thickness transplantation.

Care must be exercised in these patients and they must be aware, before surgery, that they may have a stormy course postoperatively.

In my practice, DMEK is currently the only surgical procedure I would consider to definitively restore vision loss caused by any endothelial cell dysfunction.

STROMAL TRANSPLANTATION

Modern stromal transplantation allows the surgeon to selectively replace the stroma, and vary the size and position as dictated by need. Stromal transplantation is indicated when there is any compromise to the integrity of the stroma that degrades the optical image quality and reduces vision, such as irregularity or opacity, appearing as scarring, irregularities of shape or dystrophy. Much of the current excitement of layered transplantation happened 20 years ago with stromal transplantation, but as only a handful of surgeons performed the surgery, it was a quiet revolution. The surgery is technically challenging, dealing with micro-thin tissue layers, walking the knife edge of perforating the patient’s Descemet’s, and the heartbreak of converting to a full thickness transplant. For these reasons, it has never achieved the popularity of DMEK.

The Evolution of Stromal Transplantation

The technique of replacing part of the stroma, by using crude lamellar dissectors to make a plane through the anterior stroma, has been around for more than 100 years. The dissection produced a layer of stromal tissue but left an irregular surface. When technologies such as ALK then LASIK became available, which could produce smoother, more regular corneal sections, they were tried. However, machines could only work to a limited depth in the cornea, so to head deeper into the stroma, it was back to manual techniques. The surgery acquired the acronym ‘DALK’ – for Deep Anterior Lamellar Keratoplasty – which stuck, and is still used by most people in reference to any stromal transplantation.

The question remained: how do we replace the entire stroma?

To do this, dissection had to be carried out to Descemet’s membrane, which is very fine and vulnerable to tearing or rupture, condemning the patient to a full transplant. Consider something thinner than plastic food wrap, which, when perforated, means instantaneous ‘game over’.

Descemet’s is so thin that aqueous can percolate through it, and it is prone to rupture because it has little evolutionary need for strength, but rather functions to support tiny endothelial cells. Further, the membrane is stretched in the keratoconic patient, making it even thinner and weaker. Machines are way to coarse for such fine work, and lasers send a shockwave directly into the endothelium, causing endothelial cell damage.

The answer came with surgical dissection in the pre-Descemet’s plane, also called Dua’s layer. There are two current techniques to expose this layer: the manual dissection technique of Melles, which was popularised in the late 90s, and the subsequent Big Bubble technique. My preference is the Melles technique. This gives significantly greater control of dissection and reduces the risk of rupture of Descemet’s, compared to Big Bubble, which is less controlled, with rupture risks up to 30 per cent. Currently, my rupture rate with the Melles manual technique is less than 1 per cent in my last 300 cases, which is equal or better than accepted cataract surgical complications.

With this surgery, we can now restore the evolutionary anatomy of the eye. While the surgery is challenging, exposure of this plane brings with it a sense of beauty and awe, almost like admiring a nature scene: you know you have arrived. The maturity of the surgical technique is reflected in a change in name to ‘MDALK’ or Maximum Depth Anterior Lamellar Keratoplasty.

Advantages of MDALK

The advantages of MDALK include, but are not limited to:

• The eye remains closed during surgery, eliminating serious risks such as expulsive haemorrhage

• Better surgical astigmatism control in a closed eye

• The risk of rejection of the endothelial layer is completely eliminated

• The risk of glaucoma is completely eliminated

• The risk of aqueous leak after surgery is completely eliminated

• Larger tailored transplantation can be carried out safely, including limbus to limbus transplant

• It is easy to change the transplant tissue if required

• Results in a stronger eye, reducing the risk of loss of eye with trauma

The disadvantages of MDALK are:

• It is more time consuming

• It is more difficult for the patient to understand

• It still requires sutures

• Problems of host and donor size mismatch still occur

• Drops are still required postoperatively

• Stromal rejection still occurs, although easily treated with drops

Survival of MDALK is >99 per cent,³ and all stromal transplants that I have performed including up to 20 years old, are still going strong today.

Over 10 of my patients have received accidental blunt trauma in the transplanted eye, including impacts from footballs and boxing gloves, and while ordinarily all eyes would rupture and lose sight, only one eye suffered a rupture.

One sobering reminder of the advantages of MDALK occurred over 10 years ago. I undertook a planned MDALK for a patient with keratoconus but experienced a rupture of Descemet’s membrane during surgery, forcing conversion to a full transplant. She obtained vision of 6:6 and was delighted, until years later when the eye was lost due to rupture sustained by blunt injury from domestic violence.

Almost all patients with a stromal transplant attend at some time for ‘red eye’, and almost all are told that they are ‘rejecting”. It is reassuring to be able to tell the patient on the phone that there is no reason for alarm, that they can attend for review without panic, that the cornea is most unlikely to suffer, and drops should settle the eye.

With the potential to benefit more people than the endothelial transplant, the stromal transplant has found popularity in Europe where it evolved, but is less popular in the USA, where full thickness transplantation for keratoconus is still the number one procedure (hard to believe). This is probably because the procedure is technically more challenging, with no current automated techniques, and no option for eye bank pre-cut tissue.

EPITHELIAL TRANSPLANTATION

This type of transplant remains primitive because we are indirectly transplanting stem cells. We cannot see or directly harvest stem cells, so must remove a significant amount of tissue in the hope of obtaining a few cells. It is like catching fish with a net: pull up thousands of fish and hope you get a few fish that you really want.

Epithelial stem cell transplantation is indicated when conjunctival epithelium moves onto, and displaces, corneal epithelium. The current thinking is that the problem arises due to a deficiency of healthy limbal stem cells, so to correct it, healthy limbal tissue containing stem cells is obtained from the other eye, or from donated tissue. It is almost like pterygium surgery in reverse: a section of tissue is harvested from a healthy eye and sutured into place on the surface of the damaged eye. When donor tissue is used, immune suppressant drugs are required, just like in kidney or heart transplantation, and this makes it a very complex and involved procedure for the patient. Essential to all surface disease is the use of preservative free lubricants, bandage contact lenses and sometimes a tarsorrhaphy. The desired endpoint is a smooth epithelial lining to the cornea.

THE FUTURE?

I started my career at a time when modern lamellar surgery was being developed and was lucky enough to watch Dr. Melles do his first lamellar transplants in England in 1998. I was fortunate to be able to introduce MDALK to Australia in 2000, and DMEK in 2007, and they remain my procedures of choice today. We have witnessed and been part of a surgical revolution, and any future advances to the current techniques will likely only produce marginal improvements in vision, compared to what has been achieved.

However, there remains much scope for improvement in stromal transplantation, particularly with matching donor and host shape. This is where technology like Femtosecond laser may prove beneficial in trephining recipient tissue to match the donor trephination. Until then, it remains for us to remind the patient that they must cease eye rubbing, never forget to use their drops and attend follow up as required.

It is hard to imagine where surgical improvements in endothelial transplantation will go from here. But before trying to develop newer surgeries, we must first try to improve adhesion of the tissue to speed up recovery from a few weeks to days, and look for ways to increase transplant survival. Further down the line, drug therapy or cell cloning may be the next step in cellular rehabilitation of the anterior segment.

It is hopeful that advances will be made with epithelial transplantation surgery. The corneal stem cell still eludes us, and techniques to replace it are still quite primitive. Ideally, we should be able to clone stem cells in a lab, and simply inject them into the limbus, where they can do their work. Sadly, this is still a long way off.

CONCLUSION

When there is only one solution, we offer it to everyone, irrespective of the problem: we now have the capacity to design corneal surgical solutions specifically to a patient’s needs by transplanting specific layers of the cornea, and varying size and shape according to indication. Such flexibility with corneal transplantation has been a revolution, not just because of technique, but because of what it means to patient recovery and reduction of risk.

However, transplants are not the same as cataract surgery: they are not set and forget, and require life long maintenance. The evolution to lamellar transplantation represents a significant advantage to patient vision, safety and recovery, while minimising intervention and the need for review; saving time and money. Until the last two decades, the only management option had been the full thickness corneal transplant, which inflicted on the patient a permanent degradation of vision and came with an umbilical cord that permanently attached the patient to their surgeon. Layered transplantation does not sever the umbilical cord, but it lightens it and lengthens it dramatically.

It is hard to believe that such a tiny tissue could offer so many surgical options. With improved tissue availability and reduced rejection, lamellar corneal transplantation has become a routine sight restoring procedure that is almost as universal as cataract surgery.

I have been asked by patients whether I perform full transplantation any more. Since 2000, layered transplantation has been my procedure of choice to repair and replace components of the cornea where indicated. There are circumstances where I call on a full transplant, but the indications are becoming fewer over time. After 20 years of surgery, the happiness that layered transplantation brings to both patient and surgeon is priceless.

The challenge we now face is to ensure the patient understands what we offer: from the patient’s perspective, they cannot see their problem, they can’t easily visualise the solution, and they can’t see the end result, which we are trying to deliver. Put simply, it is the problem of invisibility: the patient suffers an invisible problem, is seeking an invisible treatment, and trying to arrive at an invisible goal. Overcoming this to achieve informed consent is our greatest hurdle.

Dr. Anthony Maloof is an internationally recognised and trained surgical subspecialist in EyePlastic and Transplantation surgery, with significant contributions at national and international levels. A Fellow of the College of Surgeons and College of Ophthalmologists, Dr. Maloof offers surgery for functional and medical disease, trauma, aesthetic and rejuvenative surgery. He is appointed to Prince of Wales Hospital and Sydney Hospitals, and is responsible for trainees in his fields. Dr. Maloof regularly lectures at local and international meetings, and publishes in international scientific journals.

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References

1. Arch Ophthalmol. 2011 Nov;129(11):1435-43. doi: 10.1001/archophthalmol.2011.195. Efficacy of descemet membrane endothelial keratoplasty: clinical outcome of 200 consecutive cases after a learning curve of 25 cases. Dirisamer M, Ham L, Dapena I, Moutsouris K, Droutsas K, van Dijk K, Frank LE, Oellerich S, Melles GR.

2. Curr Opin Ophthalmol. 2013 Jul;24(4):329-35. doi: 10.1097/ICU.0b013e32836229ab. Descemet’s membrane endothelial keratoplasty surgery: update on the evidence and hurdles to acceptance. Price MO, Price FW Jr.

3. Cornea. 2012 Jun;31(6):621-6. doi: 10.1097/ ICO.0b013e31823d0412. Long-term graft survival in deep anterior lamellar keratoplasty. Sarnicola V1, Toro P, Sarnicola C, Sarnicola E, Ruggiero A.