From the rise of modern corneal graft surgery in the late 1950s until recently, corneal transplantation for keratoconus almost exclusively consisted of a full-thickness transplant, termed penetrating keratoplasty. This technique involved the removal of all of the layers of the patient's central cornea and replacement with a full-thickness graft. Over approximately the past 20 years, a quiet revolution has occurred with the development of several other types of corneal transplantation surgery for keratoconus. In addition to full thickness grafts, several different types of partial thickness, lamellar grafts, have been developed and are viable alternatives to a full-thickness graft in selected patients. The main aim of these lamellar grafts is to selectively replace the corneal stroma, leaving intact the patient's own Desçemet's membrane and endothelial cells, the main target of allograft transplant rejection. In this article, we review the current options with regard to corneal transplantation for keratoconus and review the evidence comparing newer and more established techniques.
In the field of evolutionary biology, there is a theory of punctuated equilibrium. This theory holds that rather than a slow, glacial rate of evolutionary change that evolution jumps between periods of relative stability and rapid change. The same appears to apply to the advancement of clinical practice. After decades of minimal change in the treatment of age-related macular degeneration, the field has recently changed dramatically with the introduction of vascular endothelial growth factor inhibitors. In surgical practice the same occurred in the early 1990s in the field of cataract surgery with the introduction of phacoemulsification surgery and the demise of extracapsular cataract extractions.
With the introduction of new techniques of lamellar surgery to rival the long established supremacy of penetrating corneal grafts, a similar wave of change has recently swept through the field of corneal graft surgery. This has significantly changed the surgical options for treating keratoconus as well as endothelial cell failure, where deep lamellar grafting, especially Desçemet's stripping automated endothelial keratoplasty (DSAEK), now hold sway. The technique of corneal graft surgery had largely remained static since the 1980s. Penetrating corneal grafts, more precisely referred to as penetrating keratoplasty (PKP), had reigned supreme for decades, with less than five per cent of grafts registered in the Australian Corneal Graft Registry being partial thickness, lamellar grafts. All has now changed.
Lamellar grafts have always had a great theoretical attraction, marching under the banner of ‘Replacing only the diseased part of the cornea rather than the whole,’ but how to achieve this goal? Recently, the ‘how to’ has been largely answered following an extended period of a series of blind alleys and gradual advancement. Corneal graft surgeons now have surgical techniques to selectively replace either the anterior or posterior layers of the cornea; however, this is not to say that the process of development has stopped, with new surgical techniques and refinements continuing to be trialled.
Modern deep anterior lamellar keratoplastic (DALK) techniques can deliver visual and refractive outcomes equivalent to those of penetrating keratoplasty but with preserved host endothelial cells. For the 10 to 20 per cent of patients with keratoconus unable to achieve good vision with spectacles or contact lenses, who require corneal graft surgery, this offers the very attractive theoretical advantage of totally avoiding the possibility of endothelial cell graft rejection. Several other specialised techniques have been developed to selectively replace the stroma when only the anterior stroma is affected or where the peripheral cornea is very thin.
In this article, we review the development, indications for, outcomes and application of all these techniques, with particular emphasis on the main two alternatives, penetrating and deep anterior lamellar keratoplasty. As always, it is important to remember that a corneal graft is only indicated after failing exhaustive contact lens fitting with an optometrist experienced in fitting keratoconus. Thankfully, with corneal collagen cross-linking and improvements in contact lens materials and designs, this is an ever-decreasing proportion of people with keratoconus.
Indications for Penetrating and Deep Anterior Lamellar Keratoplasty
Deep anterior lamellar keratoplasty has become the technique of choice for the treatment of advanced keratoconus, in which the posterior cornea, specifically Desçemet's membrane, is free from scarring or opacity and in which the corneal endothelium remains healthy. Penetrating keratoplasy continues to be the best choice in keratoconic eyes with deep corneal scarring, such as following previous corneal hydrops, in cases of concomitant endothelial dysfunction, such as coexisting Fuchs' endothelial dystrophy (where DSAEK is now usually performed in the absence of stromal disease) or in cases of macro-perforation during deep anterior lamellar keratoplasty. It may also be the first choice if the stroma is very thin or the cone very protuberant with marked Desçemet's membrane striae (Table 1).
Table 1. Current indications for deep anterior lamellar keratoplasty
aSelect cases unresponsive to medical treatment, not involving limbus or sclera and no intraocular spread
Corneal ectasia—keratoconus, post-refractive surgery keratectasia
Corneal stromal dystrophies—granular, lattice, Avellino and select cases of macular dystrophy
The major advantages and disadvantages of deep anterior lamellar compared with penetration keratoplasty are listed in Table 2. Principal among these is the retention of host corneal endothelial cells. This key advantage eliminates the risk of corneal endothelial cell rejection, significantly lowers rates of post-operative endothelial cell loss and will likely lead to the avoidance of late corneal graft failure due to endothelial cell loss. In addition, larger grafts that attempt to remove more or all ectatic tissue in keratoconus theoretically can be undertaken without needing to consider the risk of donor endothelial cell rejection. Successful deep anterior lamellar keratoplasty also offers the potential for more efficient use of donor corneal tissue, where one donor tissue can be used for both anterior and posterior lamellar keratoplasty or enabling use of donor material with lower endothelial cell counts. A reduced dependence on prolonged topical steroids also has numerous advantages compared to penetration keratoplasty, including reduced risk of steroid-associated intraocular pressure elevation, enhanced wound strength, reduced cataract risk and less compromise of ocular surface immunity.
Table 2. Advantages and disadvantages of deep anterior lamellar keratoplasty compared to penetrating keratoplasty (PKP)
Deep anterior lamellar keratoplasty also has some disadvantages in comparison to penetration keratoplasty. Using current techniques, it is more technically demanding and often more time-consuming than penetration keratoplasty, factors that have contributed to a slower uptake of this technique than might otherwise have been expected.
Surgically, the challenge of deep anterior lamellar keratoplasty relates to the technical difficulty of separating the posterior corneal stroma from the underlying Desçemet's membrane and associated endothelium, while still maintaining an intact host Desçemet's membrane. Several surgical modifications have been developed to separate the Desçemet's membrane from the posterior stroma.[6-11] Of these, the ‘big-bubble’ technique of Anwar and Teichmann is the most widely used (Figure 1), having largely replaced manual dissection of the deep stroma, a technique largely developed by van Dooren and colleagues. With the ‘big bubble’ technique after partial thickness trephination, deep stromal air injection forms an air bubble that aims to separate Desçemet's membrane from the overlying stroma. This greatly facilitates the removal of most or all of the overlying corneal stroma by stripping Desçemet's membrane away from the deep corneal stroma, thus generating an optically clear surface, onto which the donor lamellar tissue can be secured.
Desçemet's membrane may or may not be exposed intra-operatively by deep anterior lamellar keratoplasty, with the presence or absence of any residual host corneal stroma in the dissection bed potentially the most critical determinant of a successful outcome for deep anterior lamellar keratoplasty. ‘Desçemetic’ (or ‘maximum depth’) deep anterior lamellar keratoplasty describes the situation in which all host corneal stroma is removed and Desçemet's membrane is laid bare, while ‘pre-Desçemetic’ deep anterior lamellar keratoplasty is used to describe a case in which more than 75 per cent of the stroma is removed. Unfortunately, the literature on deep anterior lamellar keratoplasty does not always distinguish between these two variations in surgical outcomes, which is of importance because a significant stroma-to-stroma interface can generate interface haze and reduce long-term visual outcomes, as can be the case in traditional manual anterior lamellar grafts. Ideally, all cases of deep anterior lamellar keratoplasty for the treatment of keratoconus would be Desçemet's membrane-baring or ‘Desçemetic’ deep anterior lamellar keratoplasty.
Outcomes: DALK Versus PKP
Deep anterior lamellar keratoplasty and penetrating keratoplasty result in similar outcomes in terms of refractive error and visual acuity, specifically in cases where minimal or no residual host stroma remains on completion of the lamellar dissection. The risk of endothelial rejection is eliminated and while epithelial and stromal rejection may still occur, these do not pose a risk to the long-term survival of the graft. So too, as a consequence of host endothelial cell preservation, maintenance of endothelial cell density and an expected improvement in long-term graft survival will likely be the legacy of the paradigm shift from penetrating to deep anterior lamellar keratoplasty in the surgical management of keratoconus. Given the young age and long life expectancy of patients with keratoconus, and given keratoconus is the indication par excellence for deep anterior lamellar keratoplasty, such patients are likely to be the major beneficiaries of recent innovations in anterior lamellar graft surgery.
A recent systematic review of the literature evaluating findings from 1,843 eyes in 41 studies concluded that deep anterior lamellar keratoplasty yields equivalent outcomes to penetrating keratoplasty with respect to post-operative visual acuity.[1, 13-15] This applies in cases where the surgical technique yields minimal residual host stromal thickness, a factor that appears critical in determining optimal visual outcomes with this technique. By way of illustration, a recent single-centre comparative study demonstrated equivalent or better visual acuity in eyes following deep anterior lamellar keratoplasty using the big-bubble technique compared with penetrating keratoplasty but inferior visual outcomes in cases using a manual pre-Desçemetic deep anterior lamellar keratoplasty. Others have correlated visual outcomes after deep anterior lamellar keratoplastic keratoconics with the thickness of the residual host stroma, reporting that a residual stromal thickness of less than 20 μm achieved visual outcomes similar to eyes after penetrating keratoplasty, while those with deep anterior lamellar keratoplasty and a residual stromal thickness of more than 80 μm had significantly reduced visual acuity. It is worth noting that in such cases, while vision was reduced in the deep anterior lamellar keratoplasty group compared to the group with penetrating keratoplasty, there was less than one line of Snellen acuity difference on average between the groups. A reduction in visual acuity between penetrating and deep anterior lamellar keratoplasty has frequently been attributed to ‘interface opacity’. This refers to a reduction in clarity at the interface between the graft and the host tissue.
There is no significant difference in post-operative spherical refractive error or astigmatism between eyes with penetrating or deep anterior lamellar keratoplasty, with mean astigmatism of between 4.00 and 5.00 D.[1, 17] This is not surprising given that both the lamellar and penetrating techniques have very similar requirements from a suturing perspective to secure the donor tissue.
Graft survival following penetrating keratoplasty for keratoconus shows very high rates of success, with one large series reporting a survival rate of 97 per cent at five years and 92 per cent at 10 years. More extended follow-up reported by the Australian Corneal Graft Registry demonstrates graft survival rates for primary penetrating keratoplasty in keratoconic eyes of 89 per cent at 10 years, 49 per cent at 20 years and 17 per cent at 23 years. While these data are encouraging, they do indicate that a young person with a penetrating corneal graft for keratoconus is likely to require repeated keratoplasty. This is significant given that second and subsequent grafts have a shorter survival than the first graft.
Recent data demonstrate early confirmation that deep anterior lamellar keratoplasty offers better graft survival rates than penetrating keratoplasty. In the largest reported series evaluating graft survival after deep anterior lamellar keratoplasty, which included 448 eyes with keratoconus, they reported an average graft survival rate of 99.3 per cent at a mean follow-up of 4.5 years. While this is encouraging, given the relatively short time in which modern deep anterior lamellar keratoplasty has been used, the true effect of retaining host corneal endothelial cells on long-term graft survival will not be known for decades. Data from the most recent report of the Australian Corneal Graft Registry found a higher rate of graft failure early on in the post-operative course for deep anterior lamellar keratoplasty compared to penetrating keratoplasty; however, there was some suggestion that after this the rate of graft failure for deep anterior lamellar keratoplasty was lower.
Common or serious complications associated with deep anterior lamellar keratoplasty are discussed hereafter. Some of these, such as intra-operative perforation of Desçemet's membrane or a double anterior chamber, are unique to deep anterior lamellar keratoplasty, while others also occur in penetrating keratoplasty (Table 3).
Table 3. Complications of deep anterior lamellar keratoplasty
Desçemet's membrane perforation and conversion to penetrating keratoplasty
A recent systematic review of the literature found intra-operative perforation of Desçemet's membrane to be the most commonly reported complication of deep anterior lamellar keratoplasty, occurring at an average rate of 11.7 per cent with an intra-operative penetrating keratoplasty conversion rate of 2.0 per cent. Such a low rate of intra-operative conversion suggests that the vast majority of cases of deep anterior lamellar keratoplasty are completed as intended. Risk factors for intra-operative perforation of Desçemet's membrane and intra-operative conversion to penetrating keratoplasty are postulated to include the degree of stromal thinning in keratoconus, variations in surgical technique and the surgical learning curve in initial cases. Intra-operative perforation of Desçemet's membrane represents an increased risk of conversion to a penetrating keratoplasty as well as the post-operative formation of a false anterior chamber.
One of the key advantages of deep anterior lamellar over penetrating grafts relates to the preservation of host corneal endothelial cells, with a consequent elimination of the possibility of endothelial graft rejection. The importance of this advantage is underscored by the fact that endothelial graft rejection is an important contributor to graft failure after penetrating keratoplasty and remains a significant risk factor for graft failure following penetrating grafts for keratoconus.[18, 19]
Stromal and epithelial graft rejection, while less common and a less significant threat to long-term graft survival, can still occur in deep anterior lamellar keratoplasty, as in eyes after penetrating keratoplasty. A recent study of 129 eyes treated with deep anterior lamellar keratoplasty for keratoconus reported 14 (10.9 per cent) episodes of sub-epithelial graft rejection and four episodes (3.1 per cent) of stromal graft rejection. All cases were successfully treated with a short course of topical steroids. Most rejection episodes in this study (n = 13) occurred in patients with a history of vernal keratoconjunctivitis.
Endothelial cell loss
Current evidence consistently demonstrates that endothelial cell loss after uncomplicated deep anterior lamellar keratoplasty is significantly lower than that following penetrating keratoplasty. An initial accelerated rate of endothelial cell loss in the first six months following deep anterior lamellar keratoplasty appears to stabilise and return to baseline thereafter for periods up to 10 years.[1, 17, 24] Endothelial cell loss may be more marked in complicated cases of deep anterior lamellar keratoplasty, in which intra-operative microperforation of Desçemet's membrane occurs, or in cases requiring anterior chamber injection of air to manage detachment of Desçemet's membrane or double anterior chamber.[25-28]
Long-term data for endothelial cell loss following penetrating grafts is available and demonstrates significantly higher rates of loss and over a more extended period.[29-32] In a proposed biexponential model of endothelial cell loss, a rapid component of cell loss is said to occur over the first four years following penetrating surgery, with an additional slower component of endothelial cell loss continuing at a rate higher than in healthy eyes and which may be related to sub-clinical immune endothelial rejection.[1, 33]
Given that patients with keratoconus who require corneal transplantation tend to be young with a long life expectancy, it is just these patients who stand to gain the maximum benefit from a technique such as deep anterior lamellar keratoplasty that preserves host endothelial cells and seems likely to extend graft survival in comparison to penetrating grafts. Further clinical studies with longer follow-up periods are required to establish longer-term rates of endothelial cell loss following deep anterior lamellar keratoplasty and better evaluate any associated advantage in terms of graft survival.
Complications at the lamellar graft-host interface are a feature that is unique to lamellar keratoplasty. A recent systematic review of the literature on deep anterior lamellar keratoplasty suggests that while complications affecting the graft-host interface can reduce visual outcomes, they are uncommon with interface haze reported in approximately 0.7 per cent of cases, Desçemet's membrane wrinkling in 0.5 per cent and interface vascularisation in 0.5 per cent.
In summary, deep anterior lamellar keratoplasty is an exciting technique that continues to evolve and which offers a number of substantial theoretical and confirmed advantages over penetrating keratoplasty in the treatment of patients requiring corneal graft surgery for keratoconus. A role for penetrating grafts in some patients with keratoconus still remains, especially in those with previous hydrops, deep scars or very thin ectatic cones and this is likely to remain the case for some time.
Special Corneal Graft Techniques for Keratoconus
Penetrating or deep anterior lamellar keratoplastic techniques are sufficient for treating the vast majority of people with keratoconus requiring corneal graft surgery; however, sometimes the corneal thinning extends too far toward the limbus, or the preferred activities of the patient may place them at high risk of graft dehiscence. In such cases, other specialised, less commonly performed grafting techniques may be indicated.
‘Tuck in’ lamellar keratoplasty
In cases with extreme corneal ectasia extending close to the limbus, conventional corneal grafting may not be appropriate. Large-diameter full-thickness grafts are not recommended, as they are associated with a high risk of allograft rejection and secondary glaucoma. To circumvent these issues, Kaushal and colleagues reported ‘tuck in’ lamellar keratoplasty (TILK), which involves a central lamellar corneal transplantation with intrastromal tucking of a 1.5 to 2.0 mm partial-thickness peripheral flange (Figures 2 and 3). The central 8.5 mm part of the graft provides visual rehabilitation similar to a regular lamellar keratoplasty, while the peripheral flange tucked into the intrastromal pocket integrates into the host and provides tectonic (structural) support to the peripheral cornea. ‘Tuck in’ lamellar keratoplasty gives good results in terms of wound profile, post-keratoplasty astigmatism and visual outcomes.
Femtosecond laser-assisted lamellar keratoplasty
The concept of the manual technique of ‘tuck in’ lamellar keratoplasty can be applied to femtosecond laser-assisted, ‘top-hat’ keratoplasty. The femtosecond laser is able to make precise corneal incisions with customised graft edges for both donor and recipient corneas (Figure 4). The resultant ‘shaped keratoplasty’ may result in a stronger wound profile than that achieved with standard penetrating keratoplasty. Chan and colleagues reported results of femtosecond laser-assisted deep anterior lamellar keratoplasty in seven eyes of seven patients (six with corneal ectasia) using ‘mushroom’ configuration incisions. The authors reported good visual outcomes using this surgical technique.
Although femtosecond laser-assisted surgery may well become a viable option for patients with keratoconus, important issues still exist. Many of these cases have variable stromal thickness, especially patients with advanced keratoconus and corneal ectasia. The presence of deep stromal scars may limit the ability of the femtosecond laser to produce a uniform lamellar plane, while leaving a minimal amount of residual corneal tissue. Perhaps the most significant issue relates to the interface achievable with current femtosecond software and technology. While femtosecond lasers are routinely used for the creation of laser in situ keratomiluesis (LASIK) flaps with excellent results, these same results are not generally seen with deeper corneal incisions, as the resulting interface is frequently less clear, leading to reduced clarity and visual acuity.
While the preliminary results of femtosecond laser-assisted lamellar corneal surgery with current technology are encouraging,[36, 37] they are currently not equal to those of penetrating or deep anterior lamellar keratoplasty.
Microkeratome-assisted anterior lamellar keratoplasty is another useful procedure for keratoconic corneas with minimum corneal thickness of 380 microns or more. This technique largely overcomes the disadvantages of deep anterior lamellar or other manual lamellar keratoplastic techniques, as it is technically less demanding and therefore, more easily reproducible. The technique involves the use of an automated lamellar therapeutic keratome (ALTK; Moria SA, Antony, France) that employs a gas turbine-driven microkeratome to perform both the recipient and the donor lamellar cuts with the use of an artificial chamber. The host cornea is prepared by removing the anterior 250 microns with the help of the microkeratome. The depth of the cut is controlled by the choice of the appropriate microkeratome head. The donor tissue is prepared by mounting the tissue on an artificial anterior chamber and removing the anterior 300 to 350 microns with the microkeratome. This tissue is then punched to size and the posterior layer may be used for another patient with endothelial disease. The donor tissue is then sutured onto the host bed. The major advantage of microkeratome-assisted keratoplasty includes a smooth graft-host interface and a significantly reduced risk of corneal rupture from blunt ocular trauma.
Some reports claim visual results that are at least as good as penetrating keratoplasty. Tan and Ang presented a ‘two stage’ ALTK procedure to control the diameter of the flap that is cut during donor and host dissection. The recipient corneal lamellar bed is prepared by performing a conventional, superiorly hinged 9.5 mm LASIK flap with the use of a 180 μm head Hansatome microkeratome. The second stage is performed two months later by performing a partial-thickness 8.0 mm circular trephination centred within the LASIK flap, at a depth of 200 μm and then suturing the donor lenticule to the recipient bed. Using this technique, vertical graft edges can be obtained instead of shelved edges produced by the conventional ALTK system that may result in inaccurate edge apposition between the donor and recipient during graft suturing.
More recently, Busin and colleagues described the modified ‘microkeratome-assisted lamellar keratoplasty’ for keratoconus. The surgical technique is essentially the same as conventional microkeratome-assisted anterior lamellar transplantation except that the surgeon performs a full-thickness trephination of the recipient bed before suturing the donor graft in place (Figures 5 and 6). This is done to ‘collapse’ the cone in patients with keratoconus. The trephination is full-thickness; however, the incised tissue is retained, and hence this remains a lamellar technique. It is proposed that this collapse of the residual bed eliminates its mechanical resistance, thus providing better astigmatic outcomes and consequently better visual results.
Microkeratome-assisted lamellar surgery shares all the advantages of other lamellar corneal transplantation techniques. The surgery is reproducible with a reduced chance of complications, when compared to other techniques, such as ‘big-bubble’ deep anterior lamellar keratoplasty. Long-term outcomes for patients with keratoconus are exciting in terms of visual recovery and astigmatism.
Similar to penetrating and microkeratome-assisted anterior lamellar grafts, microkeratome-assisted ‘mushroom keratoplasty’ restores corneal clarity in eyes with full-thickness corneal disease (Figure 7). This surgery consists of a large, 9.0 mm diameter anterior lamellar graft, combined with a small, 6.5 mm diameter posterior lamellar graft, resulting in a mushroom-shaped penetrating graft with a large anterior ‘hat’ and a small posterior ‘stem’. Mushroom keratoplasty offers the refractive advantage (that is, less astigmatism) of a large penetrating graft, combined with the immune advantage (that is, increased survival) of a small penetrating keratoplasty. In addition, a stronger wound profile is achieved compared to that resulting from a conventional one-piece penetrating graft.
Mushroom keratoplasty is indicated for full-thickness corneal opacities in the presence of a healthy endothelium. In the setting of keratoconus, it is most useful for thin corneas that may not be appropriate for other techniques, such as big-bubble deep anterior lamellar keratoplasty or corneas with healed scars from corneal hydrops.
Mushroom keratoplasty combines the optical advantages of large penetrating grafts with the high survival rate of small penetrating grafts, while leaving the patient with a graft that theoretically has greater tectonic support than a conventional penetrating graft.
Over the past decade, a revolution has taken place in corneal graft surgery. For the treatment of keratoconus, this has meant that from having just one surgical procedure, namely, penetrating keratoplasty to offer all patients, we now have a number of lamellar techniques that can also be fitted into the treatment paradigm. The revolution is not over, the field continues to develop and it is easy to see a time in the near future, where these lamellar techniques will largely replace penetrating keratoplasty for the treatment of keratoconus. Indeed, we are already almost there. Hopefully, this will result in improved outcomes for our patients, especially an increase in corneal graft survival due to a reduction in the rate of graft rejection.