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Background
Face transplantation entails partial or full replacement of a patient's face with a donor's face. The patient's face is removed and replaced, including the underlying fat, nerves and blood vessels, but no musculature. Thus, face transplantation does not give the patient's face the appearance of the deceased donor's face because the underlying musculature and bones are different. Individuals with faces disfigured by burns, cancer extirpation, trauma, or congenital birth defects might benefit from the procedure, which consists of a series of operations with issues of age, sex, skin color, and tissue type. In some cases, face transplantation may improve patients' basic functions (e.g., breathing, eating, speaking, and swallowing). The surgery may take 8 to 24 hours, followed by a 10 to 14 days hospital stay. Following the transplantation, a lifetime regimen of immunosuppressants is needed to prevent rejection. Long-term immunosuppression increases the risk of the development of life-threatening infections, kidney damage, and cancer. The surgery may result in complications such as infections that would require a second transplant or reconstruction with skin grafts. Psychological effects of the procedure may include disappointment, remorse, or grief/guilt toward the donor.
Dubernard and colleagues (2007) performed the first human partial face allograft on November 27, 2005 and reported outcomes up to 18 months after transplantation. The post-surgical induction immunosuppression protocol included thymoglobulins combined with mycophenolate mofetil, prednisone, and tacrolimus. Donor hematopoietic stem cells were infused on post-operative days 4 and 11. Sequential biopsy specimens were taken from a sentinel skin graft, the facial skin, and the oral mucosa. Functional progress was assessed by tests of sensory and motor function performed monthly. Psychological support was provided before and after transplantation. Sensitivity to light touch, as assessed with the use of static monofilaments, as well as sensitivity to heat and cold had returned to normal at 6 months after transplantation. Motor recovery was slower, and labial contact allowing complete mouth closure was achieved at 10 months. Psychological acceptance of the graft progressed as function improved. Rejection episodes occurred on days 18 and 214 after transplantation and were reversed. A decrease in inulin clearance led to a change in immunosuppressive regimen from tacrolimus to sirolimus at 14 months. Extracorporeal photochemotherapy (ECP) was introduced at 10 months to prevent recurrence of rejection. There have been no subsequent rejection episodes. At 18 months, the patient was satisfied with the esthetic result. The authors concluded that in this patient who underwent the first partial face transplantation, the functional and esthetic results 18 months after transplantation were satisfactory.
Lantieri and associates (2008) reported a 1-year follow-up of a patient who underwent face transplantation with a composite tissue allograft (CTA). On January 21, 2007, a 29-year old man with neurofibromatosis type 1 underwent resection of a massive plexiform neurofibroma that infiltrated diffusely the middle and lower part of his face. The main goal was to restore both the cutaneous appearance and functions of the face, including, in particular, control of orbicularis oculi and oris muscle contraction. The issues of immunosuppressive therapy, psychological outcome, and social re-integration were addressed, together with the monitoring of graft rejection by biopsies of the skin and mucosa. The initial post-operative course was uncomplicated; 2 episodes of clinical rejection occurred on days 28 and 64. The second episode was associated with cytomegalovirus (CMV) infection. Both episodes resolved favorably, with no further clinical signs of rejection, making the reduction of immunosuppressive treatment possible. A year after surgery, the functional outcome was very good, with successful sensory and motor re-innervation in the transplanted territory. Psychological recovery was excellent, with complete social re-integration. The authors concluded that this case demonstrated the feasibility of surgically removing a large part of the face and replacing it with a CTA. This facial repair procedure, which seems to have a satisfactory risk-to-benefit ratio, could be offered in rare and selected cases.
Guo and associates (2008) performed a partial facial transplant in 2006, and reported the 2-year follow-up of the patient. The patient was mauled by a bear in October 2004. Allograft composite tissue transplantation was done in April 2006 after careful systemic preparation. The surgery included anastomosis of the right mandibular artery and anterior facial vein, whole repair of total nose, upper lip, parotid gland, front wall of the maxillary sinus, part of the infra-orbital wall, and zygomatic bone. Facial nerve anastomosis was done during the operation. Quadruple immunomodulatory therapy was used, including corticosteroids, mycophenolate mofetil, tacrolimus, and humanized IL-2 receptor monoclonal antibody. Follow-up included T lymphocyte subgroups in peripheral blood, pathological and immunohistochemical examinations, functional progress, and psychological support. Composite tissue flap survived well. There were 3 acute rejection episodes at 3, 5, and 17 months post-transplantation, but these were controlled by adjustment of the tacrolimus dose or the use of methylprednisolone pulse therapy. Hepatic and renal functions were normal, and there was no infection. The patient developed hyperglycemia on day 3 after transplantation, which was controlled by medication. The authors concluded that facial transplantation could be successful in the short-term, but the procedure was not without complications. However, promising results could mean that this procedure might be an option for long-term restoration of severe facial disfigurement.
Siemionow and co-workers (2009) described an innovative approach entailing a single surgical procedure of face allograft transplantation that is a viable alternative of multiple reconstructive procedures. In December 2008, a 45-year old woman with severe mid-face trauma underwent near-total face transplantation in which 80 % of her face was replaced with a tailored CTA. After the operation, the patient did well physically and psychologically, and tolerated immunosuppression without any major complication. Routine biopsy on day 47 after transplantation showed rejection of graft mucosa; however, a single bolus of corticosteroids reversed rejection. During the first 3 weeks after transplantation, the patient accepted her new face; 6 months after surgery, the functional outcome has been excellent. In contrast to her status before transplantation, the patient can now breathe through her nose, smell, taste, speak intelligibly, eat solid foods, and drink from a cup. These researchers showed the feasibility of reconstruction of severely disfigured patients in a single surgical procedure using composite face allotransplantation. Thus, this approach should be taken in consideration as an early option for severely disfigured patients.
Siemionow and colleagues (2010) noted that a total of 9 face transplants have been performed since 2005. Multiple esthetic subunits (i.e., eyelids, lips, nose) with or without underlying cranio-facial skeletal defects (i.e., mandible, maxilla) have been successfully restored, thereby providing restoration of vital facial functions (e.g., smiling). As of today, face transplantation carries an estimated 2-year mortality of 20 %. Concomitant CTA, which involves a variable combination of allograft subtypes, has been performed in 2 of the 9 face transplant patients. These have included simultaneous bilateral hand transplants and tongue with mandible. The authors concluded that more studies are needed to examine the potential advantages and disadvantages of using this approach versus a staged approach for reconstruction.
Lantieri et al (2011) reported the reproducibility, difficulties, serious adverse events and outcomes of their patients who had undergone face transplantation. Five patients were included in a registered clinical research protocol after thorough screenings assessed by an independent expert committee that discussed systematically the alternative options. One patient suffered from plexiform neurofibromas, 2 from third-degree burns and 2 from gunshot injuries. They were included on a national waiting list with a dedicated face procurement procedure. Transplants were harvested from heart beating brain-dead donors before other tissues and organs. Induction immunosuppressive therapy included anti-thymocyte globulins, steroids, mycophenolate mofetil and tacrolimus. Maintenance therapy included steroids, mycophenolate mofetil, tacrolimus, and ECP. Four patients were transplanted with 7- to 38-month follow-up. One could not undergo facial transplantation due to multiple panel reactive antibodies after 18 months on the waiting list. Acute cellular rejections were controlled by conventional treatment. Opportunistic infections affected all patients and resulted in the death of a patient 2 months after the transplantation. Voluntary facial activity appeared at 3 to 5 months following transplant. The authors concluded that face transplantation has been reproducible under conventional immunosuppression. Major improvements in facial esthetic and function allowed patients to recover social relations and improved their quality of life.
Pomahac and colleagues (2011) reported the functional and anatomical restoration 1 year after face transplantation. A 59-year old man with severe disfigurement from electrical burn injury was treated with a facial allograft composed of bone and soft tissues to restore mid-facial form and function. An initial potent anti-rejection treatment was tapered to minimal dose of immunosuppression. There were no surgical complications. The patient showed facial redness during the initial post-operative months. One acute rejection episode was reversed with a brief methylprednisolone bolus treatment. Pathological analysis and the donor's medical history suggested that rosacea transferred from the donor caused the erythema, successfully treated with topical metronidazol. Significant restoration of nasal breathing, speech, feeding, sensation and animation was achieved. The patient was highly satisfied with the esthetic result, and regained much of his capacity for normal social life.
Petruzzo et al (2011) evaluated all allograft structures by histology, magnetic resonance imaging, ultrasonography and high resolution peripheral quantitative computed tomography scan in 4 bilateral hand-grafted patients (10, 7, 3 and 2 years of follow-up, respectively) and in 1 facial allotransplantation (5 years of follow-up). All the recipients presented normal skin structure without dermal fibrosis. Vessels were patent, without thrombosis, stenosis or intimal hyperplasia. Tendons and nerves were also normal; muscles showed some changes, such as a variable degree of muscular hypotrophy, particularly of intrinsic muscles, accompanied by fatty degeneration that might be related to denervation. In the majority of hand-grafted patients graft radius and recipient tibia showed a decrease in trabecular density, although in the graft radius the alterations also involved the cortices. No deterioration of graft function was noted. In these cases of CTA no signs of chronic graft rejection have been detected. However, the possibility that chronic rejection may develop in CTA exists, highlighting the necessity of close continuous follow-up of the patients.
Vasilic and Kon (2011) noted that CTA is a new development in reconstructive surgery that makes it possible to use identical tissue to repair large mutilating deformities (e.g., the face). Until now, a total of 13 face transplants have been performed worldwide. The functional and esthetic results are encouraging. However, the lifelong immunosuppressive therapy necessary to prevent rejection has considerable side effects.
Gordon et al (2011) stated that CTA is fraught with complexities similar to those of solid organ transplantation, including donor-related CMV transmission. With this in mind, the authors' objective was to (i) report their team's experience with infections and donor-related CMV transmission in relation to face transplantation, and (ii) review the facial CTA literature as it pertains to CMV and other various infections. A Medline literature search and article review was performed in July 2010 on all published articles specific to face transplantation, CMV disease, and all related infections and/or complications. In addition, the authors retrospectively reviewed their own institution's experience with face transplantation. Two of the world's first 4 face transplant recipients acquired CMV viral infection by means of their donated facial organs. Also, the French experience, and the authors' own, has been challenged by CMV re-activation and graft rejection, therefore necessitating a critical evaluation. These researchers have also learned from their own experience that facial CTA containing mucosa and para-nasal sinuses present a distinct challenge with regard to their accompanying flora. The authors concluded that although the risk of donor-derived CMV is acceptable in life-saving solid organ transplantation, for face transplantation patients, the scenario is different. When the authors' team performed the first nearly total face/maxilla transplantation (December 2008), there was little known regarding the consequences of CMV-related donor transmission in face transplantation. Therefore, the authors now recommend that all candidates be fully informed as to the risks of CMV/infectious transmission and that aggressive viral, bacterial, and fungal prophylaxis be instituted.
Morris et al (2007) noted that 3 years ago, the Working Party of the Royal College of Surgeons of England on Facial Transplantation concluded that until there was more information available about risks any potential patient would be exposed to, it would be unwise to proceed with transplantation of the human face. Over the last 3 years, there has been a deepening understanding of the potential psychological problems of facial transplantation as well as a very considerable debate on the ethical aspects of the procedure. Further data on experimental work in animal models of facial transplantation as well as medium-term follow-up data from 24 hand and forearm transplants in 18 patients has now become available. Furthermore, a partial facial transplantation has been performed in France and a second one in China. In this second edition of the report, the technical, immunological, psychological, and ethical issues were discussed again in light of this developing knowledge. In particular, there has been a major expansion of the sections on the psychological and societal issues, as well as the ethical and legal problems of facial transplantation. The report cited the many psychological issues that face transplant recipients must confront, including unrealistic expectations, the risk of devastating transplant failure, and the reactions of others to their altered appearance. Face transplantation also entails “invasive press interest and publicity”. While updated experience with hand transplants as well as the French face transplant recipient suggested that close monitoring and treatment adjustments can head off problems with acute rejection, the risks of chronic rejection remains unknown. The Working Party still has considerable reservations about facial transplantation. Although it accepts that on balance the risks can not be precisely quantified, they remain substantial. Thus, if patients are allowed to make an informed choice to proceed, they must be very carefully selected and protected in the process, along with the families of both the donors and the recipients. To achieve this, the Working Party insists that 15 minimum requirements must be fulfilled before it would be appropriate for a research ethics committee/institutional review board to approve of a proposal to undertake facial transplantation.
Chenggang and colleagues (2008) reviewed some issues associated with facial transplantation, especially focusing on the individual who underwent the transplant in the authors' department. These investigators discussed surgical indications, techniques, risks versus benefits, informed consent and psychosocial, societal and financial issues of facial transplantation. In their opinion, with the progresses in CTA, partial or full facial transplantation is becoming a timely and effective remedy for the significantly disfigured patients. However, there are a lot of unsolved problems, and as these researchers have performed the transplant on only 3 patients, no long-term outcome data are available. The authors stated that facial transplantation needs further research.
Mathes et al (2009) examined the current attitudes about the emerging field of CTA from those who treat complex facial injuries. In 2007, a Web-based blinded survey was sent to both burn and plastic surgeons involved in facial reconstruction. These researchers examined the practice profile with regard to complex facial injuries and asked respondents to assess the level of risk in CTA and indications for facial transplantation. Surgeons were asked to evaluate 3 clinical cases (2 closely mirroring clinical face transplantations) for suitability for treatment with CTA. A total of 164 surgeons responded (54 % response rate) and averaged 17.3 years in practice. They saw 12.1 severe facial-injury patients per year. A total of 78.7 % agreed that current techniques do not provide adequate reconstruction for severe facial injuries, and 26.2 % were in favor of performing CTA on immunosuppression. Acceptable indications for CTA were multiple failed reconstructions (70 %), total facial burn (59 %), and absence of remote tissue (55 %). Ten percent saw no acceptable indication for CTA. The scenarios that mimicked recent transplantations had moderate support in favor of CTA (20.7 % for the Chinese patient and 29.3 % for the French patient). The authors concluded that this survey demonstrated support for use of CTA to reconstruct complex facial deformities. Surgeons continue to be wary of immunosuppression and chronic rejection, and many want to wait for better immunologic treatment options.
Siemionow and Gordon (2010) stated that it must be emphasized that face transplantation is still experimental and its therapeutic value remains to be validated. All surgical teams pursuing this endeavor must dedicate an attention to detail and should accept a responsibility to publish their outcomes in a transparent manner in order to contribute to the international field. However, due to its inherent complexity, facial transplantation should only be performed by university-affiliated medical institutions capable of orchestrating a specialized multi-disciplinary team with a long-term commitment to its success.
Unlike other organ transplantations, much is unknown about the long-term side effects of face transplants. The known risks are similar to other organ transplantation procedures such as a need for lifelong immunosuppressive medications, diabetes, lymphoma, risk of infection, and risk of rejection. While many other organ transplantations (e.g., heart or liver transplantation) are life-saving, face transplantation is a non-life saving reconstructive procedure. Moreover, face transplant recipients need to take immunosuppressive drugs for the remainder of their lives and, despite dramatic improvements in the safety of modern immunosuppressive protocols, they continue to suffer from adverse effects, a fact which raises ethical doubts regarding the legitimacy of face transplantation given its non-life saving nature. Furthermore, the effectiveness of immunosuppressive treatment in preventing chronic rejection remains unclear.
The CTA Working Group of the European Society for Organ Transplantation (Schneeberger et al, 2011) stated that more than 60 hand/forearm/arm transplantations as well as 16 face transplantations have been performed in the past 12 years. In the European experience, 3 grafts have been lost in response to a vascular thrombosis (n = 1), rejection and incompliance with immunosuppression (n = 1) and death (n = 1). The overall functional and esthetic outcome is very satisfactory, but serious side effects and complications related to immunosuppression are challenges hindering progress in this field. The high levels of immunosuppression, skin rejection, nerve regeneration, donor legislation and the acceptance level need to be addressed to promote growth of this promising new field in transplantation and reconstructive surgery.
Pomahac and colleagues (2011) stated that face transplantation has the unique potential to restore facial form and function in patients with severe facial defects. Current indications for face transplantation remain limited by unknown long-term outcomes and the requirements for life-long immunosuppression and substantial plans for reconstruction in case of failure. These investigators initially obtained Institutional Review Board approval for partial face transplantation in patients with defects comprising 25 % of the face and/or loss of 1 or more major facial features. They launched an outcome-oriented face transplantation study and screened 13 potential patients between February 2008 and January 2011. Experience gained during screening motivated the expansion of indications to include full facial defects and the consideration of patient-specific complex issues on a case-by-case basis. Although the authors' program focuses on restoring absent or severely compromised motor and sensory functions, they recognize aesthetic appearance as a crucial facial function. Patients are extensively educated on the risks and benefits of facial transplantation and then allowed to play the main role in the decision-making process, as long as no absolute exclusion criteria are present. As more data about the long-term outcomes of face transplantation and safe reduction of immunosuppression are gathered, face-transplant indications may expand from major unreconstructable defects towards potentially minor defects.
Siemionow and Ozturk (2012) stated that since 2005, 17 facial allo-transplantations have been performed worldwide. These investigators presented a brief summary of current cases with ongoing concerns. A total of 15 publications were reported for 10 facial allo-transplantations. For the remaining 7 transplantations, information was gathered from scientific meeting presentations and media releases. The summary of current cases in terms of etiology, indications, results, complications, and outcomes were based on these data. The discussion of ongoing concerns, controversies, and overview of future implications was accomplished by reviewing the literature of ethical debates, experimental studies, clinical studies, and personal opinion. Two of the 17 face transplant recipients died. Overall survival rate was 88 %. No early graft loss due to technical failure was reported. All reported cases that have more than 1-year follow-up had at least 1 acute rejection episode, which was reversible with treatment. Opportunistic infections and metabolic complications were observed as adverse effects. Motor recoveries were slower than the sensorial recoveries, as expected. Functional and aesthetic outcomes were satisfactory. Concerns and controversies about concomitant face and hand transplantation, recipient blindness, recipient age, primary reconstruction option in facial trauma cases, funding, graft failure risks, and future treatment options were discussed. The authors concluded that because of uncertainty about long-term outcomes, immunosuppression-related concerns and ethical debates limit world-wide application of facial allo-transplantation. However, in selected group of patients, it is an unique reconstruction method with promising outcomes. They stated that further research and investigation in transplant immunology and treatment hold the key to advance this treatment option.
The need for lifelong immunosuppression and unpredictable functional outcomes preclude face transplantation from routine acceptance in clinical practice. There is currently a clinical trial at the Brigham and Women's Hospital (Boston, MA) that aims to develop the best practices for facial transplantation, which will improve the outcomes of future face transplant recipients. The estimated number of enrollment is 5; and the estimated study completion date is February 2012. The inclusion as well as exclusion criteria of this clinical trial are as follows:
Inclusion Criteria:
- Age between 18 and 60 years
- Loss of a major part of the face (e.g., the nose or the lips, or at least 25 % of the facial tissue)
- Signed written informed consent
- The facial defect can not be restored with traditional reconstruction techniques
- Willing to complete psychological and social evaluations
- Willing to take immunosuppressants for life
- Willing to return for follow-up visits as determined by the treating physician and to comply with extensive post-transplant rehabilitation therapy
- Willing to receive standard vaccinations prior to the transplant (e.g., influenza and hepatitis B)
Exclusion Criteria:
- Absence of adequate donor sites for skin grafting in the event of transplant failure
- Active malignancy
- Any diagnosis that puts the subject at risk during the face transplant surgery
- Findings of psychological evaluation that indicate inability to comply with physician's orders or mental instability
- High risk of return of malignancy
- History of persistent non-compliance
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