Introduction
The notion of drastically improving the treatment of catastrophic facial injuries, regardless of the cause, has motivated surgeons to pursue the development of facial transplantation in addition to other types of vascularized composite allotransplantation (VCA) over the past few decades. Historically, the reconstruction of such daunting facial defects has been demanding, often requiring numerous procedures and often yielding less than ideal results. Conventional techniques have been largely inadequate to restore facial aesthetics and function in these severe injuries, while the reconstruction of anatomically and functionally complex facial structures such as the nose, lips, and eyelids has been especially disappointing. Despite significant effort and treatment, these patients are often left with lifelong functional and aesthetic handicaps.
The first facial transplantation in the world took place in Amiens, France in 2005. In the decade since, there have been nearly 30 reported full or partial face transplants performed in over a half dozen countries and several more that have not yet even been reported. The first patient was a 38-year-old woman who sustained severe injuries to the lips, nose, and cheek from a dog bite. The early results from this procedure were remarkable, in that it provided the entire world with a medical breakthrough and gave hope to patients with facial defects considered “unreconstructable” by conventional methods. Since then, several other facial transplantations have been performed and the encouraging outcomes of these cases have also demonstrated the amazing potential to restore facial aesthetics and function that was previously impossible with traditional reconstructive techniques. However, the enthusiastic outlook toward facial transplantation among the medical community has recently become more guarded, given that three of the transplant patients have died. The first patient died of unknown causes in China, secondary to his refusal to take immunosuppressive medications, while the second patient was a severely burned patient, who received a simultaneous bilateral upper extremity and facial transplantation and died of sepsis 1 month after his procedure. The third confirmed death after facial transplantation occurred in an HIV-positive patient as a result of tumor recurrence after a prior cancer resection. In addition to these tragic deaths, several minor complications have been reported, including infections with opportunistic organisms and steroid-induced diabetes mellitus. Despite these issues, the fact that the long-term outcomes of facial transplantation are unknown and the fact that this procedure is still largely considered experimental, there remains an excitement among reconstructive surgeons and patients alike about this powerful new technique.
The practice of organ transplantation is associated with a variety of ethical issues, including the limited availability of donors, the risk of rejection, and the importance of informed consent for both donors and recipients alike. On top of these issues, there arises an additional set of new ethical dilemmas for facial transplantation related to the potential transfer of a person’s appearance or identity as well as the risk–benefit ratio of the procedure. Concerns regarding self-identity are based on the recognized role of facial features in perceptions of identity and self, as well as our dealings with others. Critics of facial transplantation might argue that a disruption in self-recognition may lead to regret, depression, and potentially even life crises. On the other hand, a loss of self-recognition is likely to already be present in candidates for facial transplantation due to their pre-existing facial disfiguration. Additionally, facial transplantation may help candidate patients further regain their lost sense of identity, by giving them the ability to communicate emotions through facial expressions, which may in fact be more important to a sense of identity than facial contours and features. The early results from the first few cases of facial transplantation performed demonstrate that transplant recipients do in fact regain much of their social capacity and even accept the allograft as part of their own body.
Unlike solid organ transplantation, facial transplantation is mainly performed in patients with an otherwise normal life expectancy. However, the required immunosuppressive therapy is likely to shorten life expectancy because of untoward side effects. Furthermore, rejection and loss of the allograft would require replacement with a new allograft or reconstruction by conventional techniques, with likely inferior results. When balancing the risks and benefits of facial transplantation, the social stigmatization experienced by those patients with severe facial disfigurement must be considered as an acceptable facial appearance is important for normal social interactions. As a result, patients with severe deformities have been willing to accept the risks given the potential of the procedure to vastly enhance their quality of life.
Facial transplantation is an extraordinarily complex and resource-demanding undertaking, with the potential to change a patient’s life for the better after a disfiguring accident. A multidisciplinary team is necessary to address all the different aspects of the preparation, procedure, and follow-up. Potential candidates for facial transplantation need to undergo vigorous physical and psychological testing preoperatively. A diverse surgical team is also needed, with expertise in head and neck reconstruction, microsurgery, craniofacial surgery, and transplant surgery. Close follow-up with a battery of tests, as well as daily therapy sessions are needed postoperatively. This chapter aims to shed some light on the exciting and expanding new field of facial transplantation.
Immune Suppression
As with any type of allotransplantation, the composite tissue allograft will be recognized as foreign tissue by the recipient’s immune system, which will lead to immunologic rejection. At the time of writing, this can only be prevented by lifelong immunosuppressive therapy, which carries with it significant risks and side effects. Compared with the transplantation of a solid organ, such as a kidney or liver, which could be considered lifesaving, the risks and side effects of these medications must be weighed seriously against the non-lifesaving nature of facial transplantation procedures. Once the surgical feasibility was established, the immunologic problem has become the main obstacle against VCA of all types. As a result, the continuous need for the development of new and improved immunosuppressive therapies is of paramount importance to VCA.
Allograft rejection is the process where the transplanted tissues are attacked by the recipient’s immune system after it has been recognized as foreign and therefore potentially harmful. Rejection is caused by a genetic incompatibility between components of the recipient and donor tissues. These incompatible components are known as antigens. It is these antigens, along with antigen presenting cells (APCs) and T-cells, that are the three major players in allograft rejection. Less commonly, other tissues in the recipient’s body may be attacked by components of the donor’s immune system that have been harbored in the allograft. This is known as graft-versus-host disease (GVHD).
Immunosuppressive therapy typically begins immediately after surgery (induction therapy) to prevent the rejection of transplanted composite tissues and must continue (maintenance therapy) under close monitoring, as long as the graft remains viable. Induction therapy is essential to delay the onset of acute rejection while allowing for maintenance agents to reach their therapeutic levels. Table 64.1 outlines the main agents used for both induction and maintenance therapy at our institution. Maintenance therapy is typically a tri-agent therapy. Rescue therapy is provided to patients during episodes of acute rejection and initially starts with corticosteroid boluses. If this is unsuccessful, the antibody agents used for induction therapy can be used in addition. In contrast to solid organ transplantation, topical forms of some agents such as corticosteroids or tacrolimus, can be used as rescue agents in face transplantation.
| Induction Therapy | ||
| ATG | 1.5 mg/kg | POD 0–4 |
| MP | 1000 mg/day | dbs |
| 400 mg/day | POD 0 | |
| 200 mg/day | POD 1 | |
| 160 mg/day | POD 2 | |
| 120 mg/day | POD 3 | |
| Maintenance Therapy | ||
| Prednisone | 60 mg/day | POD 4–5 |
| 20 mg/day | POD 6–current | |
| MMF | 1000 mg/day | dbs |
| 2000 mg/day | POD 0–current | |
| TAC | 10–15 ng/mL | POD 0–30 |
| 8–10 | POD 31–current | |
Acute Rejection
Acute rejection may be mediated by either antibodies or by cells. When antibody is mediated in nature, the antibodies are against donor tissues and may have been formed either before or soon after the transplant has taken place. In some cases, patients have preformed antibodies resultant from a previous blood transfusion, solid organ transplant, or pregnancy. The antibodies bind to small peptides on the surface of the graft, triggering the immune response and reducing graft survival. Cell-mediated acute rejection involves both CD4 and CD8 T-cell subtypes, as well as macrophages that infiltrate the interstitial and vascular components of the allograft, inflicting injury.
Chronic Rejection
Chronic rejection poses the single greatest threat to the survival of a transplanted allograft. It is a slow, chronic deterioration that compromises the function of the allograft. Histologically, the parts of the graft affected will become fibrotic and changes in the vasculature are seen as well. The fibrosis is primarily the result of a low-grade inflammation, which stimulates fibroblasts to deposit excessive amounts of collagen as well as other components of the extracellular matrix. The changes in the vasculature are believed to be the result of antibody mediated rejection. Both immunologic and non-immunologic events are believed to cause the development of chronic rejection. Acute rejection episodes, sensitization, and noncompliance with immunosuppression are some of the main immunologic events implicated. Non-immunologic events linked to the development of chronic rejection include significant past medical problems such as diabetes, hypertension, lipid abnormalities, and viral infections. Often, patients undergoing VCA tend to have a less remarkable past medical history and this is thought to be a factor contributing to the low frequency of chronic rejection in these patients.
GVHD
Genetic incompatibility between donor and recipient major histocompatibility complexes (MHCs) and tissue specific antigens can cause immunologic responses in the recipient. When the recipient’s immune system attacks the allograft, rejection is the result. On the other hand, when the donor’s immune system, transplanted with the allograft, attacks the recipient’s tissues, GVHD will result. Severe GVHD can cause death and is more likely to occur after the transplantation of hematopoietic stem cells rather than solid organs. GVHD occurs in approximately 1–2% of solid organ transplantations. Not enough data is available to estimate the risk of GVHD in facial transplantation but it is presumed to be similar or lower than that for solid organ transplantation. Risk factors for developing GVHD include advanced age, immunodeficiency at time of transplant, and similar human leukocyte antigen (HLA) match.
Immune Tolerance
Immune tolerance is the ideal state of a recipient of an allotransplantation. It is defined as the absence of immune response by the recipient to the allograft tissue. Ideally, this means that the recipient can tolerate the graft even in the absence of immunosuppressive medications. The achievement of such donor-specific immune tolerance remains elusive today. It has been reported to occur rarely, often spontaneously, and by mechanisms not well understood. This remains an area of intense research interest and which could revolutionize the field of transplant medicine once understood in greater detail.
Side Effects of Immune Suppression
Unfortunately, despite their necessity in VCA, immunosuppressive medications are fraught with side effects. Chief among them are increased incidence of infections, cancer, and renal toxicity. Other reported side effects associated with immunosuppression use in patients who have undergone VCA include metabolic derangement, diabetes, hypertension, Cushing syndrome, and rarely, avascular necrosis of the hip. Not enough data exist to precisely identify the incidence of side effects associated with immunosuppressive medications such as tacrolimus, in patients who have undergone facial transplantation; however, these rates have been well established in patients undergoing renal transplantation, as seen in Table 64.2 . Early data with VCA seem to suggest that there is a lower incidence of renal failure and diabetes in this patient group.
| Side-effect | Incidence (%) |
|---|---|
| Abdominal pain | 29–59 |
| Anorexia | 34 |
| Constipation | 23–35 |
| Diarrhea | 37–72 |
| Glucose intolerance | 24 |
| Headache | 37–64 |
| Hyperlipidemia | 31 |
| Hypertension | 38–89 |
| Insomnia | 32–64 |
| Nausea | 32–46 |
| Tremors | 15–56 |
| Paresthesia | 17–40 |
| Pleural effusion | 30–36 |
| Vomiting | 14–29 |
Opportunistic infections represent perhaps the most common side effect associated with immunosuppressive medications in VCA patients. The current treatment approach involves having a high index of suspicion, liberally using laboratory tests and providing early treatment. Approximately 63% of patients undergoing hand transplantation were affected by an opportunistic infection at a median follow-up time of 81 months. Rates of bacterial infection may be comparable between hand transplant patients and renal transplant patients with a trend toward increased amounts of fungal, protozoal, and viral infections in patients undergoing hand transplant. The infection rate after facial transplantation is reported in approximately 1 in 4 patients.
Although, the available literature on VCA seems to suggest that the side effect rate of immunosuppressive drugs is lower than originally perceived, there remains a need for further research to facilitate the safe reduction of the immunosuppressive load.
Indications
In the future, face transplantation may become the treatment of choice for patients with considerable functional and social impairment, as a result of severe facial disfigurement. These disfigurements often are very large, involving more than 25% of the surface area of the face and usually involve more than just one of the aesthetic subunits of the face. The detailed and intricate anatomic characteristics of the structures destroyed in these disfiguring incidents are often impossible to completely restore with traditional reconstructive techniques. As a result, the transplant of a facial allograft presents surgeons with a unique opportunity to restore not only the form but also the function of these damaged structures to patients.
Severe facial disfigurement can be the result of a wide array of causes. Prominent causes include, but are not limited to trauma, burns, congenital defects, infections, and cancer. For example, the first two face transplants ever performed were to correct traumatic defects caused by the violent attacks of a dog and a bear. Face transplant operations have been performed in the United States for disfigurements caused by high-voltage electrical burns, chemical burns, animal attacks, as well as for a traumatic defect caused by a shotgun blast. Additionally, face transplantation has been performed on two patients to correct defects resultant from neurofibromatosis. As indicated by these few cases, there is a particular set of challenges and difficulties associated with each patient and the reconstruction of their unique defect based on its cause.
Trauma and Burns
Nearly one-third of all trauma cases annually in the United States involve facial trauma, with motor vehicle collisions representing the most common cause. The impact caused by such accidents is capable of generating enough force to produce severe facial injuries at times. Such high-speed, high-energy crashes may result in defects of the face that are severe enough to warrant facial transplantation.
In the civilian population, whether accidental, self-inflicted, or the result of a violent crime, gunshot wounds to the face represent another high-energy traumatic defect with a wide extent. For patients who survive these traumas, they often have severe facial disfigurement, despite undergoing several complex reconstructive procedures. Face transplantation may be the only treatment option in these patients with the potential to restore both a more socially acceptable facial appearance, as well as a potentially restoring facial function.
Similarly, survivors of extensive burns often have excessive scars and contractures, which have significant functional limitations by restricting range of motion. This issue is compounded by the fact that acute burn care has made considerable progress in the past decades. As the survival rates increase, there are more and more patients with high percentage body surface area burns, as well as facial burns who are seeking reconstruction. In patients with severe burns to the face, functional limitations are magnified and reconstructive options are often limited. The resulting deformities on these patients can significantly hinder social interaction by impairing the patient’s facial appearance and expression.
Many of the aforementioned groups of patients undergo numerous complex reconstructive procedures to improve their quality of life and unfortunately, have less than ideal outcomes. For these patients, face transplantation may offer a solution to their previously unconquerable problem. Several potential advantages of face transplantation include not only restoring facial appearance and function, but also potentially decreasing the number of surgical procedures necessary to reconstruct the patient. Additionally, it may reduce the time needed to be spent in a rehab facility and likely would also accelerate reintegration of the patient back into society.
The Military
The continued improvement in the acute care of wartime injuries, coupled with improvements in body armor have allowed soldiers to survive wounds that were previously fatal. As a result, more than half of all combat injuries and one-fifth of all noncombat injuries are to the head, neck, and face. Additionally, due to the increased usage of improvised explosive devices, the face is among the most frequently burned body areas on soldiers in combat, most probably due to lack of protective coverings. The severe facial defects seen in military personnel as a result of hostile environments and lethal weaponry are ideally suitable for reconstruction with facial transplantation.
Congenital Defects
Congenital and craniofacial defects are a major source of serious facial disfigurement. Even after numerous complex reconstructive procedures patients with congenital syndromes such as Treacher–Collins syndrome and rare craniofacial clefts, among others, may continue to lack a normal appearance. Furthermore, large vascular malformations or benign tumors of childhood, such as facial neurofibromas, may grow until they become massive, causing significant facial disfiguration. Adults with these facial disfigurements may derive great benefit from face transplantation. Of note, at the current time, facial transplantation has not yet been performed in the pediatric population, given concerns over the toxicities associated with immunosuppressive medications.
Infectious Disease
Numerous infectious agents can produce disfiguring facial defects. Patients can develop necrotizing infections in the skin and mucosa that can become highly invasive and spread to deeper underlying structures. For example, noma (cancrum oris), is a rapidly progressive, polymicrobial infection, which begins as necrotizing gingivitis that rapidly spreads along facial tissue planes. Severe defects or even death can result if unrecognized and untreated. With any infectious etiology, the process must be halted and the pathogen completely eradicated before considering face transplantation.
Malignant Disease
Many forms of cancers that affect the head and neck are highly invasive. These tumors can often grow to involve a large number of structures. Resection of such tumors has resulted in extensive defects, which have traditionally been reconstructed with autologous tissue. Unfortunately, the aesthetic and functional result is usually suboptimal, despite the best surgical efforts when the tumor involves units of the face such as the eyelids or lips. These delicate structures were previously felt to be “unreconstructable” with conventional methods. This group of patients stands to benefit greatly from face transplantation. The most important issue in this patient group is the strict adherence to oncologic treatment protocols and a complete removal of all tumor burden before transplantation is attempted. Similar to solid organ transplants, a patient would be considered a candidate for facial transplantation only if they were free of disease burden for at least 5 years.
Future Indications
At the present time, current indications for face transplant are limited only to facial disfigurements or defects in adults, that are large because of the risks associated with immunosuppressive regimens. As less toxic immunosuppressive medications are developed, the risk–benefit ratio of performing a face transplantation will dramatically decrease. Thus, the potential exists for even smaller, complex facial defects to be reconstructed with allograft tissue transfer, rather than autologous tissue, thereby completely eliminating any donor site morbidity. Ultimately, the rate limiting step to its widespread use will be the supply of donors.
In the future, facial transplantation might also be performed in the acute setting, closely following the initial injury. At the present time, this is a controversial issue, but may be ideal for future patients where the indications for transplantation are clear. To date, only one such procedure has been performed in Poland on a 33-year-old man, who was injured in an industrial accident.
Furthermore, because of the risks associated with immunosuppressive medications, facial transplantation is limited to the adult population at this time. As the newer medications are developed that have a lower side effect profile, face transplant may become a viable option in the pediatric population. This might allow children with congenital craniofacial deformities to grow and develop without the social stigma of facial disfigurement.
Preoperative Considerations
Patient Selection
Given its current status in most centers as an experimental procedure with uncertain long-term outcomes, the selection of patients for facial transplantation may be just as important as actually performing the surgical procedure. Furthermore, since the operation itself and the immunosuppressive medications pose a significant risk to patients, the importance of strict indications and exclusion criteria cannot be overstated. The ideal patient should have severe facial disfigurement not amenable to reconstruction with conventional techniques, and they should be of general good physical and mental health, with solid social support. The recipient must not only be healthy enough to endure the stress associated with such an operation but must also comply with lifelong immunosuppression and be willing to engage in aggressive rehabilitation during the first 2 years postoperatively, to regain function of the allograft. The ability to handle the publicity and attention generated by such a groundbreaking operation must also be considered. As facial transplantation in most centers is being performed within the confines of clinical studies, all potential candidates in those centers must be approved by the Institutional Review Board. The complex nature of the screening process requires the development of a multidisciplinary team, led by plastic and transplant surgeons. Table 64.3 summarizes the sequential patient screening process for facial transplantation used at our institution.
| Initial evaluation with reconstructive plastic surgeon | |
|---|---|
| Inclusion/Exclusion criteria reviewed | |
| ↓ | |
| Psychosocial evaluations by psychiatry and social work | |
| Inclusion/Exclusion criteria reviewed | Psychosocial support |
| ↓ | |
| Consent | |
| To lab tests and imaging | To screening procedure |
| ↓ | |
| Transplant clinic screening | |
| Information on immunosuppression | Immunologic screening |
| ↓ | |
| Rehabilitation consult | |
| Information on postoperative therapy protocol | Assess current needs of patient |
| ↓ | |
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