Challenges, opportunities and controversy in keratoplasty

Prior to the mid-1960s, corneal transplantation was viewed as an infrequently performed procedure associated with a guarded prognosis. Indications for the procedure were limited. Most successful cases involved central scarring, keratoconus and superficial stromal dystrophy. Stromal edema and endothelial dysfunction were rarely attempted and were followed routinely by graft failure.

The procedure involved general anesthesia and several days hospital stay. Scheduling was difficult since cases had to be performed on an emergency basis, within a few hours of the death of the donor, to maintain the viability of the corneal endothelium. Corneal preservation was rudimentary and consisted of placing the enucleated globe in a refrigerated moist chamber. There were no trained eye bank technicians and donations of tissue usually depended on the prior signing of a ‘donor card’. In more than one US state, eyes were obtained following the execution of condemned prisoners. There were few groups involved in ‘eye banking’. Lay fraternal organizations, such as the Lions Club, were often involved in sponsoring these activities. One of the most active eye banks depended on morticians performing enucleations and the process of obtaining informed consent from surviving relatives was cumbersome and time consuming. There were no accepted standards or regulations relating to retrieval, storage, evaluation, determination of suitability for transplantation or for avoiding disease transmission.

There were no trained corneal surgeons; all ophthalmologists were generalists and few had any basic science or research training. The importance of the corneal endothelium to the functional capacity of the successful graft was not universally appreciated. Instrumentation was rudimentary, often placing the endothelium at risk during the procedure. Free-hand techniques were common in the preparation of donor material, often using the square graft format popularized by Ramon Castroviejo [1]. 6–0 black silk sutures were standard and topical steroids were not used routinely. Patients were placed in the prone position and maintained on bed rest for several days, often with their head stabilized by sand bags.

Wound leaks, iris prolapse and frank graft dehisance were common. Inflammation was often accompanied by graft failure. In those instances where a clear graft was obtained, astigmatism often prevented adequate acuity. The relationship between surgical technique and secondary astigmatism was poorly understood. There was little expertise in fitting contact lenses and, where available, they were often difficult both to fit and to wear. While allograft rejection was not uncommon, its treatment was often delayed and inadequate. One of the most frequent indications for keratoplasty was previous graft failure. Glaucoma was a fairly frequent complication and its detection was often delayed by the inability to access intraocular pressure in the early postoperative period.

Yet, within 10 years, corneal transplantation had become transformed as a result of the combination of a number of advances. Eye banking became a more medically oriented activity, associated with hospitals and teaching institutions. Individual banks were funded adequately with the costs covered by third party payers. The Eye Bank Association of America and Tissue Banks International evolved into successful umbrella organizations involved in the standardization of collection, inspection, processing, storage and disposition of donor tissue. Medical standards were developed, technicians trained and the US FDA assumed a regulatory role. Many US states developed donor legislation that eased the process of tissue donation. Laboratory advances, from cryopreservation to a variety of improved tissue culture media, increased the acceptable storage time, enabling more efficient scheduling and disposition of tissue [2,3].

The availability of operating microscopes led to the development of microsurgical techniques, instrumentation and monofilament nylon suture material with sharp, swaged needles, all of which contributed to improved techniques and results [4,5]. Trephines and corneal punches became available and the technique of punching the donor tissue from the endothelial side was accepted quickly as a means of protecting this delicate monolayer.

Corneal fellowship training became available and cornea specialists became widely available. Topical antibiotics and steroids and hydrophilic bandage lenses contributed to graft survival [6].

Long-acting local anesthetics were developed that, combined with newer sedation techniques, resulted in a shift to local anesthesia. Following the publication of a series of outpatient procedures in the mid-1970s, ambulatory keratoplasty became the standard [7]. More conditions became amenable to successful transplantation, the number of procedures increased and the percentage of clear grafts increased concurrently. Specular microscopy was introduced and became widely available as a clinical tool to evaluate and assess the functional capacity of the diseased endothelium, as well as that of the transplanted cornea [8]. We learned that functional capacity was related more to the morphology of the endothelial cell than to the numbers of cells, yet the technique had little effect in achieving a more successful or rapid outcome following a corneal transplant [9–11].

Most of the above advances were firmly in place by the mid-1970s. Yet, a full 30 years has passed with few further advances in penetrating keratoplasty and no significant impact on visual rehabilitation or patient acceptance. In pseudophakic bullous keratoplasty, which is the most frequent indication for a corneal transplant, the rehabilitation process can approach 2 years [12,13]. Protracted wound healing associated with the elderly and in the presence of edematous corneas cannot be accelerated. The occurrence of ocular surface disease, in the form of dry eye, retarded re-epithelialization, chronic epithelial defects and bacterial ulceration, often results in additional delays, as well as a less than expected visual outcome. Regular and irregular astigmatism are too frequently the cause of reduced functional acuity. Although contact lenses have improved and are more readily available, we find that the more elderly population presents with even more challenges to successful wear. Manipulation, insertion and removal difficulties, and poor compliance are commonplace. While a number of refractive techniques have become available (relaxing incisions, wedge resection, phototherapeutic excimer laser ablation and laser in situ keratoplasty), the results are still far from good, cannot be applied uniformly and, even when implemented successfully, require months of additional rehabilitation time [14].

While concurrent developments of phacoemulsification and intraocular lens technology may have impacted on the increased need for a corneal transplant, they have not been a factor in the overall success rate or the rapidity of rehabilitation and visual restoration [15,16].

So, as we reflect upon our ability to use penetrating keratoplasty today, we realize that following a decade of great change, the improvements of the past 30 years have been incremental and have not improved outcomes greatly. Ocular surface disease, astigmatism and protracted rehabilitation continue to present challenges to both effective therapy and to patient satisfaction. As we contemplate the impact of the aging population on the potential increase in the number of disease candidates and the decreased ability of this older population to cope with the long recuperative process and the necessity of contact lens wear, we are presented with both challenge and opportunity.

With the turn of the 21st Century, much interest has developed in endothelial transplantation as a means of avoiding ocular surface difficulties as well as achieving more rapid rehabilitation. Both deep lamellar endothelial keratoplasty and the more recent stripping of Descemet’s membrane techniques have the theoretical advantage of producing less astigmatism and perhaps reducing the incidence of allograft rejection [17,18]. There is, of course, the ever-present optical problem associated with stromal interface abnormalities. These techniques are more demanding surgically and the instrumentation and surgical techniques are still evolving. For the longer term, the functional capacity of the transplanted endothelium will have to be studied, along with the incidence of true allograft rejection. Thus, the stage is set for a period of controversy as the techniques evolve. One large drawback is that candidates must have a healthy and clear stroma and the prospects for a healthy ocular surface [19].

The subset of patients with vascularized and inflamed recipient tissue, as well as those with multiple graft failure, are not candidates for these procedures. In recent years, the use of stem cell transplants as a homograft from the fellow healthy eye or, more frequently, as an allograft has had its supporters. The concept is to provide a source of healthy epithelial cells to repopulate the new graft and maintain the ocular surface. The downside of this technique is the necessity of intense topical steroid usage, often combined with systemic immunosuppression, which must be maintained for the life of the recipient. Another downside is the time factor. The stem cell transplantation process and subsequent healing must be stabilized before a traditional penetrating keratoplasty can be placed if it is to succeed.

Keratoprosthesis to implant a clear plastic optical cylinder in the diseased cornea had a brief time of limited success in the 1980s through to the early 1990s. Although these procedures were developed and designed for use in desperate cases of bilateral blindness not amenable to traditional transplantation or any other modality (chemical keratitis, autoimmune disease, dry eye syndromes and industrial trauma), there was the hope of at least a brief period of visual improvement to enable the recipient to be able to function in a limited capacity without assistance. The procedures were difficult, debilitating and, in the final analysis, associated with a high complication rate. One report suggested a 35% rate of endophthalmitis and an over 50% rate of reoperation, dislocation and frank extrusion of the prosthesis. The prostheses were secured with dental tissue, periostieum, buccal mucosa and lid skin and so constituted a significant disfigurement, as well as complicated and debilitating surgery [20]. Despite this dire set of circumstances, several individuals continued to explore newer materials, designs and potential implantation techniques, while the ophthalmic community was firm in its opinion that this was a technology associated with high risk and very low utilization. The number of clinical cases was very limited and changes were slow to come and required laborious laboratory investigations.

However, over the past 4 years, the development of the Boston keratoprosthesis has heralded a revolution in this technology. New designs with a polymethylmethacrylate device were accompanied by improved optics and the concept of implantation in donor tissue, which can then be transplanted as a traditional penetrating keratoplasty. Basic corneal physiology was respected. The optical quality of these devices approximates that of the normal eye. Both irregular and regular astigmatism are negated. There were improvements in instrumentation, as well as postoperative prophylaxis to avoid ocular surface erosion and secondary infection. This new device has been studied clinically by a number of individuals, with the greatest experience at the Massachusetts Eye and Ear Infirmary (MA, USA) and the Rochester Eye Institute (NY, USA) [21,22]. The most dramatic finding was that this particular device could be used as a primary procedure, even in an infant population, to avoid the complications associated with corneal transplants and assist in amblyopia prevention. There has been rapid rehabilitation with optimal acuity produced within weeks, no infections and complete retention of the device [23].

A protracted follow-up period and objective evaluation of potential complications, as well as the quality of vision produced and the level of patient acceptance, will be required to compare, contrast and evaluate all these techniques. Clearly, there will be advocates of the various procedures and only long-term comparative studies will resolve the emerging controversy as to the relative merits of a specific technique for particular patient populations. Thus, we are presented with the opportunity to study stem cell transplants, traditional corneal transplantation, deep lamellar endothelial keratoplasty, stripping of Descemet’s membrane and the Boston keratoprosthesis as new modalities for the alleviation of corneal opacity and the more rapid restoration of functional visual capacity. It is inevitable that this process will require years of careful observation and that it will be associated with varying interest and changing techniques. In the final analysis, the patient will benefit.