Lower extremity allotransplantation: Are we ready for prime time? Edward W. Swanson, MD1 Hsu-Tang Cheng, MD1 Denver M. Lough, MD, PhD1 W. P. Andrew Lee, MD1 Jaimie T. Shores, MD1 Gerald Brandacher, MD1
1Department of Plastic and Reconstructive Surgery, The Johns Hopkins University
School of Medicine, Baltimore, MD
Running title: Lower extremity transplantation Keywords:
Lower extremity transplantation Leg transplantation
Vascularized composite allotransplantation VCA
Corresponding Author:
Gerald Brandacher, MD 720 Rutland Avenue
Ross Research Building 749 Baltimore, MD 21205 Email: [email protected]
Phone: 410-502-9889 Fax: 410-955-9308
Disclosure:
The authors have no personal or financial conflicts of interest related to this subject matter or manuscript to disclose.
ABSTRACT
With success of upper extremity and face allotransplantation, the field of
vascularized composite allostransplantation (VCA) is preparing to expand into other reconstructive areas of the body. Lower extremity allotransplantation has the
potential to offer patients improved function over current prosthetics, reduce phantom limb pain, and reduce prosthetic associated complications. However, these benefits are weighed against the obstacles of nerve regeneration, difficult
perioperative management, and lifelong immunosuppression. Four cases of lower extremity allotransplantation have been performed with increasingly high-risk operations, marked by deaths of the last two patients. As lower extremity allotransplantation proceeds, selecting the appropriate patients to optimize outcomes is critical. We propose a clear classification system of lower extremity allotransplantation based on the extent of preservation of recipient muscular
innervation and detail the ideal next recipient. If a safe and thoughtful approach is taken, we believe lower extremity allotransplantation will achieve equivalent results to those seen in hand and face allotransplantation.
INTRODUCTION
Vascularized composite allotransplantation (VCA) has established itself as a new rung in the reconstructive ladder. Upper extremity and face transplants are
occurring on a more regular basis. Functional outcomes have been more impressive, faster paced, and continued to improve over longer time periods than previously expected. With the relative success of early vascularized composite allotransplants, newer avenues are being explored. Boundaries are being tested in terms of
combined hand/face transplants. New body regions are being considered for transplantation.1-7
The natural progression of this infantthe field is to explore the role of lower extremity allotransplantation.8 There currently are an estimated XXX number of
people with at least one lower extremity amputated in the United States. As of December 2013, 1,558 wounded warriors have returned from Iraq or Afghanistan with a major limb amputation.9 High above knee amputations and/or concomitant
upper extremity amputations make prosthetic use difficult and impractical. Poor prosthetic fit can result in recurrent pressure sores, again preventing their use.10-13
Knowledge gained from upper extremity transplantation will inform early cases of lower extremity transplantation. It is reasonable to expect similar sensorimotor recovery. The stage appears set for the next act in vascularized composite allotransplantation.
Functional recovery required for restoration of gait and balance is currently unknown, and will only be elucidated from human patients. As with upper extremity transplantation, the risks of lifelong immunosuppression must be weighed against
the function offered from current and future prosthetics. We aim to review the challenges and benefits of lower extremity allotransplantation, and through the examination of cases performed to date, attempt to construct a working framework for ideal recipients moving forward. We emphasize the need to take small
predicatable steps while the field advances, as was done with upper extremity and facial transplantation.
LOWER EXTREMITY TRANSPLANTATION CASES
Four cases of lower extremity transplantation have been carried out to date (Table 1).1-4, 14-18 Each case is outlined with details gathered from all currently available
sources, including updates at conferences and media reports.
Case 1
Zuker and colleagues completed the world’s first lower extremity transplantation in 2006.1, 2 The entire right lower extremity was transplanted between three months
old ischiopagus twins. The twins were scheduled for separation, but due to
inoperable cardiac failure of twin A (donor), emergent separation was initiated to save the life of the twin B (recipient). There were three lower extremities shared between the twins, forming a ring-like pelvis with radially oriented legs. In
transplanting the right lower extremity from twin A, twin B was provided with two normal legs, in otherwise unfortunate circumstances; the third lower extremity was removed.
The abnormal anatomy created a complex and intricate procedure, with greater considerations than lower extremity allotransplantation between two otherwise normal adults. However, the situation provided a high benefit-to-risk ratio, with no need for postoperative immunosuppression and a high potential for functional rehabilitation given the young age of the recipient. Overall, this created an ideal scenario to proceed with the first lower extremity transplantation, analogous to Dr. Joesph Murray’s first kidney transplantation between identical twin
brothers.19
Pelvic osteotomies were created to rotate the pelvis along with the hip joint from twin A into the appropriate position to form one pelvis with two hip sockets for twin B. The femoral vessels and nerve of twin B perfused and innervated the
anterior thigh muscles of the third limb, which were preserved to provide increased knee extension function to the donor limb. The donor leg vessels were dissected back to the aorta and inferior vena cava (IVC) of twin A, and ultimately anastamosed end-to-side to the aorta and IVC of twin B. The sciatic nerve of the donor limb
received contributions from both twins, and the portion from twin B was preserved. The remaining portion of sciatic nerve from twin A was connected to the sciatic stump of twin B. Finally, the previouisly isolated anterior thigh muscles (still perfused and innervated from the recipient) were connected to the quadriceps tendon of the donor limb. Additional procedures included femoral osteotomies and quadriceps tendon shortening at 2 years of age to correct abduction and weak knee extension, and semitendinosous and biceps femoris tendon transfers to augment knee extension at 6 years of age.
At 6 years of age, the transplanted limb is 6.5cm shorter than the native limb, likely due to length discrepancies at time of transplant. Sensation to light touch is present but diminished throughout the entire limb, with the greatest difference in the upper thigh; none of which causes functional impairment. Passive range of motion is near normal throughout, although active range of motion is markedly decreased. Hip flexion, knee extension/flexion, and the great toe demonstrate good strength (grade 3-4). She lacks power in plantar- and dorsiflexion. Most importantly, with bracing and shoe lift, she is able to ambulate and participate in recreational activities with her peers. Functional MRI shows cortical integration of the limb.
Case 2
Cavadas et al. completed the first adult lower extremity allotransplantation in July, 2011.3 Bilateral transfemoral transplantations were performed in a 22 year-old male
recipient. The recipient had high bilateral traumatic above knee amputations (AKA) sustained 2 years prior to transplantation following a motor vehicle crash. Pain and socket instability prevented the use of conventional prostheses and the patient refused oseointegrated prostheses due to poor experiences of peers with lower extremity amputations. The donor was a 26 year-old female multi-organ donor. The pairing was a full HLA mismatch with donor and recipient seronegative
Cytomegalovirus (CMV) status.
Donor lower extremities were harvested with vessels at the external iliac level, sciatic nerve at the level of the sciatic notch, all muscles of the anterior and posterior thighs, and osteotomies were made 22 and 12 cm proximal to the right
and left sides, respectively. Osteotomy levels were based on the recipient’s previous height and preoperative imaging. The entire body was cold perfused in-situ with Univeristy of Wisconsin (UW) solution without cross clamping. Heart and liver were procured first. The right leg was then harvested and immediately transferred to the recipient’s operating room for transplantation without further cooling. The left leg was harvested and kept cool on ice while the right leg was being transplanted. Donor limbs were perfused with warm Ringer’s solution immediately prior to
revascularization to help prevent hypothermia. Both lower extremities were repaired in the same sequence: osteosynthesis with 4.5mm locking plates, sciatic nerve epineural coaptation, muscle repair, and end-to-side external iliac
anastamosis. Ischemia times were 3.5 and 5.5 hours for right and left lower extremities, respectively.
The patient was induced with alemtuzumab and maintained with tacrolimus, mycophenolate mophetyl (MMF), and steroid taper. He incurred two Banff grade I acute rejection episodes in the first year, one related to acute CMV infection and one related to immunosuppression dose reductions. Two abscesses developed in the quadriceps, thought to be related to distal muscle ischemia, treated with
debridement and tailored intravenous antibiotics. At the time of the most recent report, he was undergoing ultrasound therapy of the left leg due to delayed bony union.
At one year follow-up, the recipient was ambulating with partial weight
bearing on parallel bars. He has full passive range of motion of both knees, with 45
3+ and 4 (MRC score) in the right and left feet, respectively. Tinel’s sign had advanced to the plantar level. Sensation and proprioception were not reported. Unfortunately, both limbs have since been removed due to neoplastic complications related to immunosuppression.20
Case 3
Ozkan and colleagues performed the world’s first triple limb transplant in Turkey in 2012.4 Unfortunately, there are no literature reports of the operation, and the only
details available are from media accounts. The recipient was a 34 year-old man who lost both arms and his right leg from an electrocution injury as a child. The donor was a man who was declared brain dead after being hit by a train. The operation lasted 12 hours. By postoperative day one, the transplanted right leg was removed due to what was reported as rejection. The patient was discharged on postoperative day 69, but ultimately died within five months from infectious complications.14, 15
Case 4
A team led by Erdem reported the world’s first attempted quadruple extremity allotransplantation.16-18 The procedure was carried out in February 2012. The
recipient was a 27 year-old man who lost all four extremities from a electrical accident at the age of 13 years. He had a left transhumeral, right shoulder level, and bilateral high above knee amputations. The donor was a 40 year-old man with a full HLA mismatch.
All four extremities, as well as the donor’s face (donated to a separate recipient), were harvested simultaneously with the solid organ transplantation teams. The limbs were perfused with UW solution. The team’s major goal was to reduce ischemia time. To accomplish their primary goal, three microsurgical teams worked simultaneously to revascularize the extremities, and the lower extremities were connected via temporary shunts while the upper extremities were definitvely reperfused. Due to the high level amputations, the team had difficulty maintaining access for both resuscitation and blood pressure monitoring. The patient endured worsening metabolic derangements intraoperatively, eventually leading to
hyperkalemia, bradycardia, and cardiac arrest at the completion of the last
anastamosis. Sternotomy and cardiopulmonary support was required to reestablish spontaneous circulation. Continuous hemodyalisis and massive transfusion (200 units) ensued over the immediate postoperative period. Each limb was sequentially amputated. The patient died on the fourth postoperative day.
Immunosuppression consisted of anti-thymocyte globulin induction and triple-drug maintenance therapy with tacrolimus, MMF, and corticosteroids. The donor extremities were irradiated due to unclear evidence of benefit in a small animal model performed at their hospital.21
The report of this case is limited and many questions are unanswered. Details of preoperative planning are incomplete. Due to the descriptions of the recipient vasculature intraoperatively, it appears there was no preoperative recipient vascular imaging. Exact management of the perfusion of the limbs prior to anastamosis is vague. Cavadas et al. described a well-planned sequential reattachment of the limbs
with re-warming immediately prior to anastamosis3; however, it seems that all four
extremities were re-perfused simultaneously with cold UW solution remaining in the limbs. No mention of preemptive transfusion for the increased blood
distribution volume was mentioned. As in Case 3, details are lacking in a situation where a significant amount of knowledge could be gained.
LIMITATIONS OF LOWER EXTREMITY PROSTHETICS
Good functional outcome can be achieved in most patients with lower extremity amputations but is largely dependent upon the level of the amputation. There is a progressive and significant lowering of physical component score (worsening
outcomes) as unilateral amputation height becomes more proximal from below knee to through knee to above knee.10 Energy expenditure in ambulation increases with
higher levels of amputation, with up to 200% increase above normal levels in patients with bilateral transfemoral amputations.11 Decreased quality of life can be
expected in patients with higher level of lower extremity amputations. Hagberg and colleagues found that the most frequently reported problems that had led to
reduction in quality of life were heat/sweating in the prosthetic socket (72%), sores/skin irritation from the socket (62%), inability to walk in woods and fields (61%), and inability to walk quickly (59%).12 Above knee amputations are one of the
statistically significant preoperative risk factors independently associated with not wearing a prosthesis.13
In an effort to alleviate problems with conventional prosthetics in transfemoral amputees, percutaneous osseointegrated prostheses were introduced in Sweden in
the 1990s.22 Implant survival was 92% after two years, with improved daily
prosthetic use, prosthetic mobility, global situation, physical function, and fewer problems. However, patients with osseointegrated prostheses commonly experience superficial infections (>50%).23
Myolectric prosthetics offer a high degree of freedom of movement using robotic technology coupled to electromyographic signals generated over target muscles.24 The limiting step in applying myoelectric prosthetics more widely is
harnessing specific, accurate, and long-lasting input. First generation myolectric prosthetics were constrained by the available functioning muscle groups, with proximal upper extremity amputees having limited input (i.e. biceps and triceps). Targerted muscle reinnervation (TMR) is one strategy to provide increased inputs by transferring available nerves to power available muscles, with native nerves providing intuitive functions to the robotic prosthetic (i.e. radial nerve extends wrist and fingers). However, TMR is still limited by available nerves and inconsistent surface electrodes.24-30 Alternative solutions include intracranial electrode placement
for brain control31-38 and highly selective peripheral nerve interfaces.24, 39-41 All
techniques are currently experimental and require further research before being used clinically.
CHALLENGES FACING LOWER EXTREMITY TRANSPLANTATION
Nerve Regeneration
One of the greatest challenges for lower extremity allotransplantation is nerve regeneration and functional recovery. As with upper extremity allotransplantation,
the best recovery and outcome can be expected for more distal transplants; however, these patients have better function with prosthetics. Nerve regeneration proceeds at 1 mm/day, and potentially faster in the presence of tacrolimus.42-51 Cavadas et al.
reports an advancing Tinel’s sign of 2.5 mm/day in the patient that received bilateral lower extremity allotransplanations.3 With leg lengths between 70-100cm,
anticipated times for nerve regeneration of an entire leg vary greatly (280-1,000 days). In cases of nerve injury with reconstruction, gains in function are rarely seen beyond one year. However, upper extremity allotransplantation patients have acquired increased motor and sensory action potentials up to 5 years
post-transplantation.42 Within that first year, regeneration is required to prevent distal
Schwann cells from becoming quiescent and from muscle atrophy and fibrosis.44
Successful strategies for improved nerve regeneration would greatly influence the risk-benefit ratio of lower extremity allotransplantation, especially cases of proximal transplantation. Taking advantage of the neuroregenerative properties of tacrolimus, fully supporting or replacing Schwann cells, and tailoring surgical technique to preserve motor/sensory fascicle anatomy and decompress known pressure points are a few approaches to optimize nerve regeneration in VCA.42, 44
In contrast to upper extremity allotransplantation, lower extremity transplants do not require significant functional recovery beyond the extrinsic muscles of the foot. Dorsi/plantar flexion and great toe extension/flexion can be achieved with muscles of the anterior and posterior compartments of the leg. In addition, leg transplanation only requires protective plantar sensation, as opposed to the goal of discriminatory sensibility in hand transplantation. Ninety percent of
hand transplant recipients have achieved tactile sensation, and cortical reintegration has been consistently demonstrated in VCA.43, 52-54
Blood Volume Re-distribution
The lower extremity comprises more than three times the percentage of total body mass when compared to the upper extremity (17-18% vs. 5-6%), depending on gender.55 Traditional Lund-Browder charts estimate the lower extremities to have
twice the total body surface area compared to upper extremities (18% vs 9%, respectively).56 Each lower extremity comprises approximately 10% of the total
body intravascular volume depending on body positioning and vascular tone.57-59
Taken together, careful consideration to fluid and blood volume status must be given prior to complete lower extremity transplantation; more so than in upper extremity allotransplantation. Preservation fluid in the donor limb will create a bolus to the rest of the body upon reperfusion. Exchange of cold preservation fluid for fresh, warm intravenous fluid immediately prior to revascularization is preferable, preventing hypothermia and metabolic imbalances. As done in the case by Cavadas et al., ensuring adequate blood volume to fill the newly added intravascular space through transfusion prior to revascularization is an important consideration.
Bilateral lower extremity transplantation complicates the picture further, and timing of reperfusion of donor limbs is critical. Case 4 highlights the complexity of adequate resuscitation and metabolic management. These issues become less of a concern when discussing more distal transplantations, as the thigh is disproportionately larger than the leg.
Lifelong Immunosuppression
As with all forms of allotransplantation, the risk of lifelong immunosuppression must be carefully weighed against the benefits of the procedure. Although experimental and clinical research is making strides towards reducing the requirements for immunosuppression, or even inducing tolerance, the current reality of immunosuppression remains.60-64 The prospect of nephrotoxicity,
hepatotoxicity, infection, and neoplastic growth are real concerns. The initial
recipients of lower extremity allotransplantation need to be selected carefully based on lessons learned from other VCA recipients.
BENEFITS OF LOWER EXTREMITY TRANSPLANTATION
Given the limitations of current and developing prosthetics, lower extremity allotransplantation offers unique benefits. With nearly all upper extremity
allotransplantation recipients achieving protective sensation,43 it is reasonable to
assume similar outcomes will be observed following lower extremity
transplantation. Discriminatory sensation would be an added benefit, but not a goal as with hand transplantation. Therefore, functional sensory recovery in lower extremity allotransplantation is expected. Blume et al. found that pain in replanted upper extremities was inversely correlated with the amount of cortical
reorganization.65 With a high degree of cortical plasticity observed in upper
extremity allotransplantation recipients and the first case of leg transplantation by Zuker and colleagues, lower extremity allotransplantation may reduce pain and
phantom limb sensations.1, 43, 52-54 The prospect of restoring protective sensation and
alleviating phantom limb phenomena not only provides benefits beyond current prosthetics, but allows lower extremity amputees to feel whole again. If patients are adequately screened and selected, and are able to develop mature coping
mechanisms, lower extremity transplantation may improve their image and self concept compared to the constant reminder of a lost limb induced by the sight of a prosthetic.66
Permanence provided by extremity transplantation avoids daily problems and decisions experienced with prosthetics. Poor fitting prostheses result in pressure sores and instability, particularly in high-level amputees. Skin irritation, socket heat, and the inability to walk quickly or on uneven terrain result in decreased prosthetic use.12, 13 Lower extremity allotransplantation will alleviate
socket-fitting issues and eliminate the choice of wearing the prosthetic.
Furthermore, a unique opportunity exists to extend amputation level from above knee to below knee to alleviate socket-fitting concerns. Extending the level of amputation distally could greatly improve quality of life. Although extension of the amputation level from above to below knee would not outweigh the risks of lifelong immunosuppression alone, such a procedure could be combined with hand or face transplantation. In contrast to the patients presented in Cases 3 and 4, combining a lower extremity amputation level extension with another form of VCA would not be expected to greatly add to the morbidity of the operation. Blood volume
re-distribution in amputation level extension would not be affected to the same degree as in proximal thigh transplantation. Additionally, amputation level extension should
only be combined with face or distal upper extremity transplants at this time to reduce complications related to increasing intravascular space. Lower extremity amputation level extension would require little motor nerve regeneration, if any, as the quadriceps are typically preserved in patients with AKA.
Overall, lower extremity allotransplantation has the potential to offer patients improved function, restoration of self, reduction in pain, and avoidance of prosthetic associated complications. Well-conceived strategies are required to optimize outcomes and gain knowledge in this experimental field.
LOWER EXTREMITY ALLOTRANSPLANTATION CLASSIFICATION
Before lower extremity allotransplantation cases accumulate, it is wise to agree upon a uniform categorization for consistent reporting and analysis of results. Lower extremity allotransplantation can be divided into levels based on motor innervation of the various muscle groups: distal leg, mid-leg, proximal leg, distal thigh, mid-thigh, and complete lower extremity transplantion (Figure 1). These levels are based on preservation of all native muscle innervation, anterior leg compartment innervation, posterior leg compartment innervation, quadriceps innervation, hamstrings innervation, and no native lower extremity muscle
innervation, respectively. As the level of transplantation moves to a more proximal level, the demand placed on nerve regeneration for motor recovery increases, with less predictable results expected. Moving to more distal levels, more muscle groups are maintained with native innervation. The best functional outcome can be
muscles of the foot, similar to a wrist level hand transplantation (Figure 1a). The transplant performed by Cavadas et al. would be considered mid-thigh level, with preserved quadriceps muscles (Figure 1d). Even with preserved recipient muscle innervation, further procedures may be required to optimize function, including tendon length adjustments and tendon transfers, as performed by Zuker et al.1, 2
CURRENT INDICATIONS FOR LOWER EXTREMITY TRANSPLANTATION
As the young field ofvarious centers are moving forward with lower extremity allotransplantation moves forward, it is important to proceed in a stepwise and safe manner. The first case by Zuker et al. was a model case for the field, with a high benefit- to-risk ratio due to no immunosuppression requirement. However, with each new case performed, there have been large leaps, culminating with Cases 3 and 4 resulting in death. Proximal levels of amputation necessitate intricate planning for staged anastamosis, resuscitation, and critical care. Combining high-level upper extremity transplantations with high-level lower extremity transplantations is ill conceived at this stage. More knowledge is needed concerning the optimal pre-, intra-, and postoperative management of high-level lower extremity
transplantations alone.
We believe that it is best to proceed with distal lower extremity
allotransplantations first, with the ability to learn about functional recovery without needing to manage a highly complex blood volume re-distribution. Only by
observing the functional recovery of distal level transplants, will we be able to decide if the benefit of proximal level transplants is worth the risk of perioperative
complications combined with lifelong imunnosuppression. The ideal next lower extremity allotransplantation candidate would be a patient requiring forearm-level upper extremity or face transplantation combined with a unilateral distal leg
transplant (Figure 2). Although there have been poor outcomes with combined VCA cases,4, 14-18, 67 selectively choosing multiple distal transplants would avoid concerns
regarding massive blood volume shifts, high antigenic burden, and large tissue mass ischemia.
Along the same lines, opportunity exists to extend amputation level from above knee to below knee for improved prosthetic function. This would allow for analysis of thigh muscle functional recovery without requiring complete lower extremity transplantation. Amputation level extension would ideally be performed in a hand transplant candidate that is a triple or quadruple limb amputee. Providing such a patient with hand function and extending the level of lower extremity
amputation would significantly improve prosthetic use and hopefully the ability to ambulate.
These two scenarios (distal leg with distal hand transplant, or above to below knee amputation level extension with distal hand transplant) may be difficult to identify, but would provide definitive answers about functional recovery with minimal added risk. It is not currently clear that proximal level lower extremity amputations are indicated, and it has been shown that combining proximal level lower extremity transplants with upper extremity transplants is unsafe. Given this, we endorse/advocate for taking small first steps as was done in upper extremity and face allotransplantation. We foresee the field ultimately proceeding to performing
transplants similar to those by Cavdas et al. (bilateral mid-thigh), but think it is wise to be selective in the near future to ensure success, safety, and to gain incremental knowledge.
CONCLUSIONS
The field of VCA is poised to move forward with lower extremity allotransplantation. Lower extremity allotransplantation offers patients the possibility of improved function, restoration of self, reduction in pain, and avoidance of prosthetic
associated complications. Improvements in nerve regeneration, fluid resuscitation, and immunotherapy would favor further expansion into lower extremity
transplantation. Lower extremity allotransplantation can be classified according to the degree of preservation of recipient muscle innervation: distal-leg, mid-leg, proximal leg, distal-thigh, mid-thigh, and complete lower extremity
allotransplantaiton. The next cases should optimize outcomes by performing distal level transplantations or amputation level extensions in order to gain knowledge of functional recovery while minimizing perioperative morbidity and mortality.
REFERENCES
1. Fattah A, Cypel T, Donner EJ, et al. The first successful lower extremity
transplantation: 6-year follow-up and implications for cortical plasticity. Am J Transplant 2011; 11(12):2762-7.
2. Zuker RM, Redett R, Alman B, et al. First successful lower-extremity
transplantation: technique and functional result. J Reconstr Microsurg 2006; 22(4):239-44.
3. Cavadas PC, Thione A, Carballeira A, et al. Bilateral transfemoral lower extremity transplantation: result at 1 year. Am J Transplant 2013; 13(5):1343-9.
4. Turkish hospital performs triple limb and face transplant [Today's Zaman web site]. January 22, 2012. Available at: http://www.todayszaman.com/news-269227-turkish-hospital-performs-triple-limb-and-face-transplant.html. Accessed September 9, 2014.
5. Berli JU, Broyles JM, Lough D, et al. Current concepts and systematic review of vascularized composite allotransplantation of the abdominal wall. Clin
Transplant 2013; 27(6):781-9.
6. Broyles JM, Berli J, Tuffaha SH, et al. Functional Abdominal Wall Reconstruction Using an Innervated Abdominal Wall Vascularized Composite Tissue Allograft: A Cadaveric Study and Review of the Literature. J Reconstr Microsurg 2014.
7. Tuffaha SH, Sacks JM, Shores JT, et al. Using the dorsal, cavernosal, and external pudendal arteries for penile transplantation: technical considerations and perfusion territories. Plast Reconstr Surg 2014; 134(1):111e-119e.
8. Carty MJ, Zuker R, Cavadas P, et al. The case for lower extremity allotransplantation. Plast Reconstr Surg 2013; 131(6):1272-7.
9. Fischer H. A Guide to U.S. Military Caualty Statistics: Operation New Dawn, Operation Iraqi Freedom, and Operation Enduring Freedom. Congress Research Service 2014.
10. Penn-Barwell JG. Outcomes in lower limb amputation following trauma: a systematic review and meta-analysis. Injury 2011; 42(12):1474-9.
11. Cuccurullo SJ. Physical medicine and rehabilitation board review. New York: Demos Medical Publishing, 2004.
12. Hagberg K, Branemark R. Consequences of non-vascular trans-femoral amputation: a survey of quality of life, prosthetic use and problems. Prosthet Orthot Int 2001; 25(3):186-94.
13. Taylor SM, Kalbaugh CA, Blackhurst DW, et al. Preoperative clinical factors predict postoperative functional outcomes after major lower limb amputation: an analysis of 553 consecutive patients. J Vasc Surg 2005; 42(2):227-35.
14. Sheets CA. Atilla Kavdir dead months after receiving triple-limb transplant in Turkey [International Business Times web site]. May 2, 2012. Available at:
http://www.ibtimes.com/atilla-kavdir-dead-months-after-receiving-triple-limb-transplant-turkey-694734. Accessed September 9, 2014.
15. Turkish double arm transplant recipient loses his life [World Bulletin web site]. May 4, 2012. Available at: http://www.worldbulletin.net/haber/89364/turkish-double-arm-transplant-recipient-loses-his-life. Accessed September 26, 2014.
16. Nasir S, Kilic YA, Karaaltin MV, et al. Lessons learned from the first quadruple extremity transplantation in the world. Ann Plast Surg 2014; 73(3):336-40.
17. Landin L, Dominguez A, Sanchez-Sanchez M. Discussion of lessons learned from the first quadruple extremity transplantation in the world: the logic of massive allograft transplantation. Ann Plast Surg 2014; 73(3):341-2.
18. Swanson EW, Brandacher G, Gordon CR. Discussion of lessons learned from the first quadruple extremity transplantation in the world: comments and concerns regarding quadruple extremity allotransplantation. Ann Plast Surg 2014;
73(3):343-5.
19. Merrill JP, Murray JE, Harrison JH, et al. Successful homotransplantation of the human kidney between identical twins. J Am Med Assoc 1956; 160(4):277-82.
20. American Society for Reconstructive Transplantation 3rd Biennial Meeting. Chicago, IL, 2012.
21. Yavas G, Yildiz F, Guler S, et al. Concomitant trastuzumab with thoracic radiotherapy: a morphological and functional study. Ann Oncol 2011; 22(5):1120-6.
22. Branemark R, Branemark PI, Rydevik B, et al. Osseointegration in skeletal reconstruction and rehabilitation: a review. J Rehabil Res Dev 2001; 38(2):175-81.
23. Branemark R, Berlin O, Hagberg K, et al. A novel osseointegrated percutaneous prosthetic system for the treatment of patients with transfemoral amputation: A prospective study of 51 patients. Bone Joint J 2014; 96-B(1):106-13.
24. Kung TA, Bueno RA, Alkhalefah GK, et al. Innovations in prosthetic interfaces for the upper extremity. Plast Reconstr Surg 2013; 132(6):1515-23.
25. Tenore FV, Ramos A, Fahmy A, et al. Decoding of individuated finger movements using surface electromyography. IEEE Trans Biomed Eng 2009; 56(5):1427-34.
26. Dumanian GA, Ko JH, O'Shaughnessy KD, et al. Targeted reinnervation for
transhumeral amputees: current surgical technique and update on results. Plast Reconstr Surg 2009; 124(3):863-9.
27. Kuiken TA, Marasco PD, Lock BA, et al. Redirection of cutaneous sensation from the hand to the chest skin of human amputees with targeted reinnervation. Proc Natl Acad Sci U S A 2007; 104(50):20061-6.
28. Kuiken TA, Miller LA, Lipschutz RD, et al. Targeted reinnervation for enhanced prosthetic arm function in a woman with a proximal amputation: a case study. Lancet 2007; 369(9559):371-80.
29. O'Shaughnessy KD, Dumanian GA, Lipschutz RD, et al. Targeted reinnervation to improve prosthesis control in transhumeral amputees. A report of three cases. J Bone Joint Surg Am 2008; 90(2):393-400.
30. Ohnishi K, Weir RF, Kuiken TA. Neural machine interfaces for controlling
multifunctional powered upper-limb prostheses. Expert Rev Med Devices 2007; 4(1):43-53.
31. Shih JJ, Krusienski DJ. Signals from intraventricular depth electrodes can control a brain-computer interface. J Neurosci Methods 2012; 203(2):311-4.
32. Shih JJ, Krusienski DJ, Wolpaw JR. Brain-computer interfaces in medicine. Mayo Clin Proc 2012; 87(3):268-79.
33. McFarland DJ, Sarnacki WA, Townsend G, et al. The P300-based brain-computer interface (BCI): effects of stimulus rate. Clin Neurophysiol 2011; 122(4):731-7.
34. McFarland DJ, Sarnacki WA, Wolpaw JR. Electroencephalographic (EEG) control of three-dimensional movement. J Neural Eng 2010; 7(3):036007.
35. Galan F, Nuttin M, Lew E, et al. A brain-actuated wheelchair: asynchronous and non-invasive Brain-computer interfaces for continuous control of robots. Clin Neurophysiol 2008; 119(9):2159-69.
36. Yanagisawa T, Hirata M, Saitoh Y, et al. Real-time control of a prosthetic hand using human electrocorticography signals. J Neurosurg 2011; 114(6):1715-22.
37. Serruya MD, Hatsopoulos NG, Paninski L, et al. Instant neural control of a movement signal. Nature 2002; 416(6877):141-2.
38. Schultz AE, Kuiken TA. Neural interfaces for control of upper limb prostheses: the state of the art and future possibilities. PM R 2011; 3(1):55-67.
39. Navarro X, Krueger TB, Lago N, et al. A critical review of interfaces with the peripheral nervous system for the control of neuroprostheses and hybrid bionic systems. J Peripher Nerv Syst 2005; 10(3):229-58.
40. Chu JU, Song KI, Han S, et al. Improvement of signal-to-interference ratio and signal-to-noise ratio in nerve cuff electrode systems. Physiol Meas 2012; 33(6):943-67.
41. Urbanchek MG, Wei B, Egeland BM, et al. Microscale electrode implantation during nerve repair: effects on nerve morphology, electromyography, and recovery of muscle contractile function. Plast Reconstr Surg 2011; 128(4):270e-278e.
42. Brandacher G, Gorantla VS, Lee WP. Hand allotransplantation. Semin Plast Surg 2010; 24(1):11-7.
43. Shores JT, Imbriglia JE, Lee WP. The current state of hand transplantation. J Hand Surg Am 2011; 36(11):1862-7.
44. Glaus SW, Johnson PJ, Mackinnon SE. Clinical strategies to enhance nerve
regeneration in composite tissue allotransplantation. Hand Clin 2011; 27(4):495-509, ix.
45. Doolabh VB, Mackinnon SE. FK506 accelerates functional recovery following nerve grafting in a rat model. Plast Reconstr Surg 1999; 103(7):1928-36.
46. Feng FY, Ogden MA, Myckatyn TM, et al. FK506 rescues peripheral nerve allografts in acute rejection. J Neurotrauma 2001; 18(2):217-29.
47. Jost SC, Doolabh VB, Mackinnon SE, et al. Acceleration of peripheral nerve regeneration following FK506 administration. Restor Neurol Neurosci 2000; 17(1):39-44.
48. Lee M, Doolabh VB, Mackinnon SE, et al. FK506 promotes functional recovery in crushed rat sciatic nerve. Muscle Nerve 2000; 23(4):633-40.
49. Gold BG, Katoh K, Storm-Dickerson T. The immunosuppressant FK506 increases the rate of axonal regeneration in rat sciatic nerve. J Neurosci 1995; 15(11):7509-16.
50. Sulaiman OA, Voda J, Gold BG, et al. FK506 increases peripheral nerve regeneration after chronic axotomy but not after chronic schwann cell denervation. Exp Neurol 2002; 175(1):127-37.
51. Udina E, Ceballos D, Gold BG, et al. FK506 enhances reinnervation by
regeneration and by collateral sprouting of peripheral nerve fibers. Exp Neurol 2003; 183(1):220-31.
52. Vargas CD, Aballea A, Rodrigues EC, et al. Re-emergence of hand-muscle
representations in human motor cortex after hand allograft. Proc Natl Acad Sci U S A 2009; 106(17):7197-202.
53. Dubernard JM, Petruzzo P, Lanzetta M, et al. Functional results of the first human double-hand transplantation. Ann Surg 2003; 238(1):128-36.
54. Frey SH, Bogdanov S, Smith JC, et al. Chronically deafferented sensory cortex recovers a grossly typical organization after allogenic hand transplantation. Curr Biol 2008; 18(19):1530-4.
55. Plagenhoef S, Evans FG, Abdelnour T. Anatomical data for analyzing human motion. Res Q Exerc Sport 1983; 54:169-178.
56. Malic CC, Karoo RO, Austin O, et al. Resuscitation burn card--a useful tool for burn injury assessment. Burns 2007; 33(2):195-9.
57. Litter J, Wood JE. The volume and distribution of blood in the human leg measured in vivo. I. The effects of graded external pressure. J Clin Invest 1954; 33(5):798-806.
58. Asmussen E. The distribution of the blood between the lower extremities and the rest of the body. Acta Physiol Scandinav 1943; 5:31.
59. Ebert RV, Stead EA. The Effect of the Application of Tourniquets on the Hemodynamics of the Circulation. J Clin Invest 1940; 19(4):561-7.
60. Gorantla VS, Brandacher G, Schneeberger S, et al. Favoring the risk-benefit balance for upper extremity transplantation--the Pittsburgh Protocol. Hand Clin 2011; 27(4):511-20, ix-x.
61. Khalifian S, Raimondi G, Lee WA, et al. Taming inflammation by targeting cytokine signaling: new perspectives in the induction of transplantation tolerance. Immunotherapy 2014; 6(5):637-53.
62. Lin CH, Zhang W, Ng TW, et al. Vascularized osteomyocutaneous allografts are permissive to tolerance by induction-based immunomodulatory therapy. Am J Transplant 2013; 13(8):2161-8.
63. Schneeberger S, Gorantla VS, Brandacher G, et al. Upper-extremity
transplantation using a cell-based protocol to minimize immunosuppression. Ann Surg 2013; 257(2):345-51.
64. Wachtman GS, Wimmers EG, Gorantla VS, et al. Biologics and donor bone marrow cells for targeted immunomodulation in vascularized composite
allotransplantation: a translational trial in swine. Transplant Proc 2011; 43(9):3541-4.
65. Blume KR, Dietrich C, Huonker R, et al. Cortical reorganization after
macroreplantation at the upper extremity: a magnetoencephalographic study. Brain 2014; 137(Pt 3):757-69.
66. Kumnig M, Jowsey SG, Moreno E, et al. Case series on defense mechanisms in patients for reconstructive hand transplantation: consideration on transplant defense concept. Ann Transplant 2014; 19:233-40.
67. Carty MJ, Hivelin M, Dumontier C, et al. Lessons learned from simultaneous face and bilateral hand allotransplantation. Plast Reconstr Surg 2013; 132(2):423-32.
TABLES
Table 1. Details of lower extremity transplantation reported to date with outcomes.
Lead Surgeon Year Details of Transplant Outcomes
Zuker1, 2 2006 Complete, unilateral lower extremity transplant
between ischiopagus twins at separation
Functioning limb 6 years postoperatively, ambulation with braces, intact sensation,
limb length discrepancy
Cavadas3 2011 Bilateral transfemoral allotransplantation Progressing function at 1 year with partialweight bearing ambulation, transplants removed due to neoplastic complications
Ozkan4, 14, 15 2012 Bilateral upper extremites, and right lower
extremity allotransplantation Deceased five months postoperatively
Tuncer16-18 2012 Quadruple limb (bilateral transhumeral and
