facial and hand allotransplantation -...

Facial and Hand Allotransplantation

Bohdan Pomahac1, Ryan M. Gobble1, and Stefan Schneeberger2,3

1Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, HarvardMedical School, Boston, Massachusetts 02115

2Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria3Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine,Baltimore, Maryland 21205

Correspondence: [email protected]

Vascularized composite allotransplantation (VCA) is a novel therapeutic option for treatmentof patients suffering from limb loss or severe facial disfigurement. To date, 72 hand and 19facial transplantations have been performed worldwide. VCA in hand and facial transplan-tation is a complex procedure requiring a multidisciplinary team approach and extensivesurgical planning. Despite good functional outcome, courses after hand and facial trans-plantation have been complicated by skin rejection. Long-term immunosuppression remainsa necessity in VCA forallograft survival. Towiden the scope of these quality-of-life-improvingprocedures, minimization of immunosuppression to limit risks and side effects is needed.

Vascularized composite allotransplantation(VCA) is a novel therapeutic option for

treatment of patients suffering from limb lossor severe disfigurement. According to the handregistry (www.handregistry.com) 41 hand trans-plantations have been performed worldwide.Of these, 21 were bilateral and 20 were unilater-al transplantations. Overall graft survival andfunctional outcome are high, but diligent sur-gery together with carefully and individuallyadjusted immunosuppressive treatment, an in-tense rehabilitation protocol, and a high levelof compliance and close patient follow-up isneeded.

Since the first partial face transplant wasperformed in Amien, France by Drs. Dubernardand Devauchelle in 2005 (Devauchelle et al.2006) a total of 19 face transplants (16 males,

three females) have been reported in the litera-ture. The largest number of transplants havebeen performed in France (n ¼ 9) followed bythe United States (n ¼ 6), Spain (n ¼ 3), andChina (n ¼ 1). Facial transplants were reportedas partial transplants in 12 cases, near-totaltransplant in one case, and full transplants insix cases. Transplants incorporated osteomyo-cutaneous components in 12 cases and myocu-taneous components in seven cases. The indi-cation for transplantation included trauma in15 cases (animal bite n ¼ 3, burn ¼ 3, ballisticn ¼ 9), congenital deformities in three cases,and tumor ablation in one case. To date, therehave been two postoperative deaths, one ofwhich occurred in a patient who had concom-itant bilateral hand transplants and succumbedto postoperative complications and a second

Editors: Laurence A. Turka and Kathryn J. Wood

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patient who was noncompliant with immuno-suppressive therapy (Siemionow and Ozturk2012). There have been no reported cases ofgraft loss, graft-versus-host disease, or hyper-acute or chronic graft rejection.

Despite good functional outcome, coursesafter hand and face transplantation have beencomplicated by skin rejection (Schneebergeret al. 2009; Hautz et al. 2012a). Long-termimmunosuppression remains a necessity inVCA for allograft survival. To widen the scopeof these quality-of-life-improving procedures,minimization of immunosuppression to limitrisks and side effects is needed.

PREPARATION AND SURGICALPROCEDURE

In preparation for hand transplantation, thestumps of the recipients should be carefullyassessed. Bone length, muscular, vascular, andnerve status can be analyzed using CT scan, an-gio-CT, angiography, magnetic resonance imag-ing, and ultrasound. This is to rule out a neu-roma at a level far proximal to the amputation.Routine workup should include blood work,X rays, electrocardiography, echocardiography,and spirometry. For exclusion of comorbiditiessuch as malignancies or infections patients un-dergo gastroscopy, colonoscopy, and dental andoropharyngeal examination (Brandacher et al.2007).

Surgical strategies in hand transplantationhave to be adapted to the level of amputationas well as the exact length and quality of struc-tures in the recipient’s stump. For each case aprecise plan and in some cases development ofnovel reconstruction techniques are required(Schneeberger et al. 2011; Landin et al. 2012).At present, definite recommendations regard-ing the maximum duration of ischemia do notexist; however, ischemia time should be keptas short as possible and not exceed 10 hours.Although cold flush and preservation withhistidine, tryptophan, ketoglutarat solution(HTK) or University of Wisconsin (UW) solu-tion might limit myocyte damage, muscles aresensitive to ischemia and damage such as inter-stitial edema, microvascular constriction, and/

or damage of myocyte membranes may result inmuscle dysfunction after 2.5 h of (warm) ische-mia (Nanobashvili et al. 2003).

All anatomic structures such as tendons,nerves, and vessels are dissected under tourni-quet control in the donor and recipient. Afterrelease of the tourniquet, the forearm is per-fused with cold HTK solution through the bra-chial artery. Next, all structures are transectedand osteotomies of the radius and ulna are per-formed. After wound closure the donor is fittedwith cosmetic prostheses.

Hand allotransplantation is then performedunder tourniquet control. After bone prepara-tion and osteosynthesis, revascularization is ini-tiated by anastomosis of one main artery andtwo veins followed by tendon/muscle repairand definitive vessel repair. Next, nerve repairis performed before skin closure. Alternatively,revascularization can be performed later afterthe extensor tendons are repaired and rapidanastomosis of one to two dorsal veins andnerve repair. Both radial and ulnar arteries arerepaired next, followed by reconstruction of theremaining veins. This is followed by flexor ten-don repair and skin closure (Azari et al. 2012).

Facial transplantation is a complex endeavorthat requires a multidisciplinary approach en-compassing the most cutting-edge aspects ofplastic surgery, transplantation immunology,and anesthesia. As no two faces are the same,no two operations are exactly the same. Thereare, however, guiding principles that should befollowed. Each operation requires an anastomo-sis to create arterial inflow and venous outflow.Also nerve coaptation is required for both mo-tor and sensory branches. Arterial and venousanastomosis as well as nerve coaptation may beeither unilateral or bilateral depending on theamount of tissue to be replaced. Osseous por-tions from the donor may be included in thecomposite tissue allograft.

Arterial inflow has been established throughthe external carotid artery, and its branches in-cluding the facial artery and the external max-illary artery, whereas venous outflow has beenachieved via the facial vein, thyrolingual fa-cial trunk, external and internal jugular vein,and the retromandibular vein. Arterial and ve-

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nous anastomoses are performed with the faceflipped down onto the recipient’s chest using amicrosurgical technique. An end-to-end anas-tomosis is preferred whenever possible and isusually able to be performed given the similarcaliber of donor and recipient vessel lumen aswell as the ease in obtaining adequate lengthvessel length from the donor (Siemionow andOzturk 2012). An end-to-side anastomosis be-tween the right subclavian and the right com-mon carotid arteries has been reported in a 42-yr-old male who underwent transplantation of35% of the face including partial bilateral cheek,upper and lower lip, chin, tongue, and mandible(Cavadas et al. 2012).

Ultimately the choice of donor and recipi-ent vessel inflow and outflow will depend on thetissues to be transplanted. It has been suggestedthat for reconstruction of tissues of the midfaceor upper face that the superficial temporal andfacial vessels are preferred, whereas reconstruc-tion of the lower face and mandible is bestachieved by using the external carotid and itsbranches, and this would certainly seem tohold true for tissue allotransplantation (Taka-matsu et al. 1996). When an osteomyocutane-ous transplant is performed more proximal ves-sels are usually preferred (e.g., external carotidartery and facial artery); however, we haveshown in a cadaver study that the facial arteryitself is capable of maintaining perfusion to theentire midface, including the maxilla, anteriorhalf of mandible from the masseter muscle in-sertion and zygoma (Pomahac et al. 2012b), aswell as the total facial allograft including maxilla(Pomahac et al. 2012a).

Full transplants deserve particular attentionwith regard to inclusion of the superficial tem-poral vessels. Inclusion of these vessels requiresinclusion of the parotid glands bilaterally, whichresults in unaesthetic fullness of the cheeks bi-laterally unless a superficial parotidectomy isperformed before transplantation, which sig-nificantly increases operative time. Includingthe parotid glands also limits facial nerve co-aptation to the level of the trunk, as the branchesof thedonor facial nerve are inaccessible. We havedeveloped a technique for full facial transplanta-tion based on only the facial arteries, which al-

lows for more target innervation of effector mus-cles without the unsightly bulges seen when theparotidglandis included (Pomahacetal. 2012b).

Most commonly, two arterial anastomosesand two or more venous anastomoses are per-formed; however, there is no definitive clinicalor experimental evidence to support recom-mendations for which vessels should be usedor how many anastomoses are required for eachtype of allotransplantation being performed.Given the high stakes of facial allotransplanta-tion, one is better served to include more thanone anastomosis when possible lest a single ar-terial or venous anastomosis become compro-mised risking loss of the entire graft. Also, giventhe nature of the recipient’s vessels as most ofthese patients have undergone multiple prioroperations and/or received prior radiation, itis wise to have a roadmap as to the nature andlocation of the recipient’s vessels. As such, pre-operative imaging including ultrasound andCT/MRI angiography should be obtained be-fore operative intervention. Preoperative CTangiography is useful for identifying the besttarget vessels for vascular anastomoses therebylimiting operative time exploring unusable ves-sels. It can alert the surgical team for the poten-tial need of vein grafts as a backup option if lessthan ideal vascular anatomy is identified preop-eratively. The key aspects in choosing the idealvessels are an optimal size match between re-cipient and donor vessels, an adequate amountof length between allograft pedicle and donorvessels, and accessibility of the pedicle (Sogaet al. 2012). Magnetic resonance (MR) angiog-raphy may be particularly useful in both pre-operative imaging with a large shrapnel com-ponent and/or postoperative follow-up oncesurgical plates have been introduced into thearea. If temporal or parietal scalp need be in-cluded preservation of the transverse facial ar-tery that connects the facial and superficial tem-poral arteries will provide adequate blood flow.If blood supply to these regions is not adequatedissection of the superficial temporal arteries inthe superficial plane at the preauricular levelmay be performed for supercharging at the re-cipients corresponding location (Pomahac et al.2012b).


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CT imaging is useful not only in planningintraoperative vascular anastomoses but alsoin planning for osteotomies in cases in whichan osteomyocutaneous transplant is performed.Brown et al. has described a cadaveric study forfull face transplant including double jaw andtongue using CT-assisted techniques when per-forming osteotomies on both the donor andrecipient (Brown et al. 2012). In this studyboth the donor and recipient cadavers wereplaced in intramaxillary fixation. Three-dimen-sional reconstructions were then superimposedon donor and recipient skulls using surgicalmodeling software. Leforte III and sagittal splitosteotomies were planed based on these projec-tions. Stereolithographic models were producedand cutting guides for Leforte III osteotomieswere made for use during the mock transplan-tation. Planned osteotomies were then import-ed into intraoperative navigation software andthe Leforte III osteotomies were performed us-ing this intraoperative guidance. CT scans per-formed after the mock transplantations showedthat accurate skeletal fixation and occlusionwas noted to be normal. Dr. Rodriguez and col-leagues were then able to translate the experi-enced gained performing these mock transplan-tations to complete the first total face, doublejaw, and tongue transplant in a 37-yr-old malewho sustained a central face high energy avulsiveballistic injury (Dorafshar et al. 2013). Use ofCT imaging to plan osteotomies during osteo-myocutaneous facial transplantation will like-ly be incorporated into future allotransplanta-tions to improve the accuracy of skeletal fixationand decrease operative times. Furthermore, useof CT imaging may help us more accurately pre-dict which donors are more likely to result in anoptimal skeletal match for facial transplant re-cipients. However, limitations in donor avail-ability will prevent passing up eligible donorsdespite a less than ideal skeletal match for theforeseeable future.

Sensory nerves used in facial transplanta-tion include the trigeminal nerve and itsbranches (e.g., infraorbital nerve, supraorbitalnerve, mental nerve, buccal sensory nerve, lin-gual nerve, inferior alveolar nerve, and cervico-facial nerve). Direct nerve coaptation of both

motor and sensory nerves using fine mono-filament suture under microscopic magnifica-tion is the preferred method; however, in casesin which trauma has destroyed the recipientsensory nerves motor coaptation alone hasbeen performed (Guo et al. 2008; Siemionowet al. 2009, 2010; Lantieri et al. 2011). Also, incases in which the mental nerves are unable tobe repaired directly the donor mental nerveshave been placed in close approximation ofthe recipient mental foramen (Lantieri et al.2008). The facial nerve serves as the motor in-put for facial transplantation. Coaptation offacial motor nerve branches at more distalsites allows for more retention of native nervelength decreasing the chances of developingsynkinesia (Pomahac et al. 2012b). Nerve graftscan be used when adequate length is not avail-able (e.g., thoracodorsal nerve, greater auricu-lar nerve).

Inset of the graft is typically performedin a central-to-lateral and inferior-to-superiorsequence. Osseous fixation is achieved usingplates as screws customized to the particularbone being fixed. Liberal use of Mitek (Burns-ville, MN) anchors in different locations in thezygoma, supraorbital bar, and mandible areused for securing the tissues of the allograft tothe underlying bony structure to provide somestructure to the face and relieve tension on thevascular anastomoses (Pomahac et al. 2012b).It is essential to achieve watertight intraoral clo-sure. The skin sutures are placed to promote theoptimal facial contour and aesthetic outcome.Drains are placed as needed depending on theamount of tissue transplanted. At our institu-tion we chose to also include a sentinel flap thatcan be used to monitor for rejection episodes.Sentinel flaps are placed at areas that requirefunctional improvements. Rejection episodeswere detected more accurately in the sentinelflap than in the facial allograft in two of ourfour face-transplant recipients (Pomahac et al.2012a). The sentinel flap is less affected by con-founding facial-skin conditions, including en-vironmental exposure or from conditions suchas dermatitis or rosacea, and is therefore felt tobe more sensitive to rejection episodes (Saave-dra et al. 2011).

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OUTCOMES

Sensitivity

Nerve regeneration after hand transplantationprogresses rapidly with nerve endings reachingthe fingertips at 6–9 months depending on thelevel of amputation/transplantation (Petruzzoet al. 2010; Hautz et al. 2011). Protective sen-sation returned in all and discriminative sensa-tion in the majority of patients. The transplant-ed hands were incorporated into the patient’sbody image in almost all patients. Protectivesensation is routinely achieved.

The outcome after forearm transplanta-tion differs significantly from the outcome af-ter hand transplantation (Schneeberger et al.2011). Particularly the time course of returnof function is significantly prolonged whencompared with hand transplantation. The func-tional outcome, therefore, needs to be read inthe light of inherit differences between handand forearm transplantation. Overall, however,despite the postoperative course being signifi-cantly more challenging when compared withhand transplantation, forearm transplantationhas also resulted in good patient satisfaction(Schneeberger et al. 2007, 2011). In additionto restoration of body integrity, improved mo-tor function and movement control and fewereveryday challenges when compared with myo-electric prostheses have been achieved. The longand intense rehabilitation protocol and the slowreturn of function require thorough and cau-tious patient selection.

Restoration of sensation in facial allo-transplantation has been assessed using severaldifferent quantitative sensory tests, includingtwo-point discrimination, Semmes-Weinsteinmonofilaments, pressure-specified sensory de-vices, and heat and cold tolerance (Siemionowand Ozturk 2012). Restoration of light touchand temperature sensation has been shown tooccur between 3 and 8 months in the majorityof cases (Dubernard et al. 2007; Guo et al. 2008;Lantieri et al. 2008; Siemionow et al. 2009; Bar-ret et al. 2011; Pomahac et al. 2012a). Lighttouch and sensation to the oral mucosa returnsaround 3 months, whereas thermal sensationdoes not typically return until 6–8 months

posttransplantation. The rate of return of sen-sation is similar to that reported with innervat-ed free flaps (Kimata et al. 1999). Documenta-tion of sensory recovery has been reported evenin cases in which direct sensory nerve coap-tation was not possible secondary to trauma(Lantieri et al. 2008). This may be owing tointerconnections between the trigeminal andfacial nerve branches that may make direct nervecoaptation not entirely necessary (Baumel 1974;Tohma et al. 2004). Although sensory recoveryhas been noted in cases in which direct nervecoaptation was not possible we still recommendits performance in all facial transplants whenpossible.

Scarring of the recipient bed has a clear neg-ative impact on sensory nerve regeneration,which will affect the ultimate outcome (Her-manson et al. 1987). Inclusion of skin within afree flap improves sensory recovery, whereasthe presence of muscle and bone may act as abarrier for neurontinization from the recipientbed (Siemionow et al. 2011). Patients with thin-ner transplants, less transplanted tissues, andyounger patients may have better sensory recov-ery (Lahteenmaki et al. 1991); however, moreclinical data with facial transplantation needsto be accumulated before this will be known.

Motor Function

In hand transplantation, motor function re-turns almost immediately after transplantation.The patient’s own forearm muscles enable fin-ger movement, which continues to increase inrange and strength over time. In many cases, thereturn of intrinsic hand muscle function canbe observed and further enhances motor func-tion. The majority of patients are able to per-form all major tasks of daily living includingholding small objects, turning pages and doorknobs, writing, and returning to work (Petruzzoet al. 2010).

As mentioned above, the functional out-come after transplantation at more proximallevels requires prolonged rehabilitation and isoverall less consistent (Landin et al. 2012). Thefunctional return in these cases may continueto improve during the first 5 years after trans-



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plantation. Although reinnervation of intrinsichand muscles has been observed in some cases,it cannot be routinely expected and the level offunction is inferior when compared with handtransplantation. Protective but not discrimina-tive sensation can be observed in the majorityof these patients. Return of hand function afterforearm transplantation requires approximate-ly 5 years to completion, as it is dependent onreinnervation and reactivation of graft forearmmuscles. Overall, hand function in forearmtransplantation remains inferior when com-pared with hand transplantation because rein-nervation and reactivation of intrinsic handmuscles are unlikely.

In cases in which the level of amputation isproximal to the elbow area, the long distancefor nerve regeneration and recovery is a majorpace-limiting factor. Only a few such cases havebeen performed and arm function in these casesis still improving at this point. Elbow functionand extrinsic finger flexion and extension havebeen satisfactory but the final and overall func-tional outcome in arm transplantation can onlybe estimated at this point (Brandacher et al.2009). More patients and long-term follow-upis needed to ultimately determine the degree offunction that can be regained in arm transplan-tation.

In all facial transplantations reported thusfar, motor recovery has occurred later and oftento a lesser extent than sensory recovery. This isunfortunate, as motor recovery will likely con-tribute more to a functionally useful and aes-thetic face. As motor recovery takes longer tooccur and motor recovery has not been docu-mented in each case we do not know exactly thefull extent of motor recovery to be expectedfollowing facial allotransplantation. However,reports from several different investigators dopaint a picture of the extent of motor recoverypossible. Dubernard et al. (2007) showed thatreturn of motor activity occurred at 3 monthsafter transplantation followed by the ability tomove the lower lip at 4 months. Their patientwas able to bring the lips into apposition at 6months and to have a full smile at 18 months.Furthermore, the patient was able to move theirnose and chin at 1-year posttransplantation

(Dubernard et al. 2007). Lantieri et al. reportedthat their patient had no evidence of facial nervereinnervation on electromyography at 3 monthsposttransplantation; however, at 1 year, therewas documented evidence of reinnervation onelectromyography (Lantieri et al. 2008). Sie-mionow et al. described an improvement in fa-cial mimetics by 6 months posttransplantationas evidenced by symmetric smiling and upperlip occlusion; however, upper lip and lower eye-lid movement were imperfect. By 1 year, theinvestigators noted almost complete motor re-covery (Siemionow et al. 2009, 2010). Barrettet al. reported an ability to move the frontalis,zygomaticus, and upper orbicularis occuli mus-cles along with unrestricted masticatory move-ment; however, their patient was unable to closethe eyes (Barret et al. 2011).

More recently we have reported on threepatients who have undergone full facial trans-plantation (Pomahac et al. 2012a). All three pa-tients recovered motor function of their face.Along with our first patient that received partialface transplant, three of four have an excellentsymmetry (Figs. 1A,B, 2A,B, and 3A,B). Onepatient has an asymmetrical smile owing to pre-vious injury of the recipient’s facial nerve, per-haps owing to traction (Fig. 4A,B).

Lack of long-term follow-up in facial trans-plantation for both sensory and motor activityremains a problem. Other difficulties in moni-toring for the return of motor activity remain anoverall lack of reporting as well as no uniformityof measuring such progress. One investigatorhas suggested using electromyographyand func-tional magnetic resonance imaging to monitorfor facial nerve reanimation (Hui-Chou et al.2010). Although these methods may becomepart of the standard for monitoring for motorrecovery they are still untested in facial trans-plantation specifically, and, for now, physicalexamination will remain the gold standard.

Peripheral Nerve Regenerationand Cortical Integration

Sensory nerve recovery for free tissue recon-struction is greater in the face than for that ofthe trunk or lower extremities in both neuroti-

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Figure 1. 26-yr-old male 12 months postfacial allotransplantation at rest (A), and smiling (B).

Figure 2. 31-yr-old male 12 months postfacial allotransplantation at rest (A), and smiling (B) .



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Figure 3. 62-yr-old male 36 months postfacial allotransplantation at rest (A), and smiling (B).

Figure 4. 58-yr-old female 12 months postfacial allotransplantation at rest (A), and smiling (B).

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nized and non-neurotinized flaps, which showsthe greater cortical representation the face re-ceives in the human homunculus (Lahteenmakiet al. 1991; Kuriakose, et al. 2001; Kerawala et al.2006; Bianchi et al. 2010).

Patient Satisfaction

Patient satisfaction is of the utmost importancein every operation, but no more so than in fa-cial allotransplantation. These patients submitthemselves to a long operation followed by aneven longer hospital stay and ultimately lifelongimmunosuppression. For a successful outcomepatient buy in is essential. As previously shownrestoration of sensation takes many months,whereas return of motor activity can take overa year. Despite all of these obstacles patient sat-isfaction remains very high. Several investiga-tors have noted restoration of olfaction and anability to eat and drink within a week postop-eratively (Dubernard, et al. 2007; Lantieri et al.2008; Siemionow et al. 2009; Pomahac et al.2012a). Patients who had been previously fedvia gastrostomy tubes were able to have themremoved and tracheostomy-dependent patientswere able to be decanulated (Siemionow andOzturk 2012). Furthermore, improvement inspeech has been noted with transplantation ofthe hard palate and the use of an obturator(Siemionow et al. 2009; Pomahac et al. 2011).

Patient-specific questionnaire studies are yetto be performed, but most investigators reportthat their patients are happy with their out-comes. Results from a psychosocial analysis ofquality-of-life measures using the MOS-SF-12showed that patients at our institution who un-derwent facial allotransplantation had a signifi-cant improvement in their mental health in the6 months posttransplantation (Chang and Po-mahac 2012). Clearly for patients requiring fa-cial transplantation the devastating nature oftheir injuries severely limits their ability to in-teract in society, and improvement both aes-thetically and functionally is welcome. Ethicalconcerns remain, given the risk of death with theoperation along with the risk of developing ma-lignancy with the need for lifelong immuno-suppression. Furthermore, access to care issues

and an overall lack of donors make this life-al-tering procedure available only to a select groupof patients.

IMMUNOLOGICAL ASPECTS

Immunosuppression

The immunology in VCA is characterized bythe strong skin-directed immune response, themarkedly different gravity of the immune re-sponse against the different tissues, and the abil-ity to visually monitor the skin (Cendales et al.2008; Hautz et al. 2012b). The failure of the firsthuman hand transplantation reported in 1964was caused by the strong immune responseand the lack of modern immunosuppressivetherapy (Gilbert 1964). Transplantation of theskin was considered impossible until hand andface transplantation was performed successful-ly after 1998. At this point, the side effects oflong-term high-dose immunosuppression rath-er than rejection represents the remaining pace-limiting obstacle in this field (Hautz et al. 2010a;Brandacher et al. 2012). Two patients died fol-lowing a combined hand and face transplanta-tion and attempted bilateral upper and lowerextremity transplantation (Lantieri et al. 2011;Daily Mail Reporter 2012). Rejection remainsa challenge and threat, but the morbidity causedby the required drug treatment is limiting thelarger-scale application of this nonlifesavingtreatment. Concurrent with the advancementsin solid organ transplantation, minimizationor elimination of the need for long-term high-dose and/or multidrug immunosuppression isthe primary goal of global research in this novelfield. A reduction of maintenance immunosup-pression has recently been achieved in a smallclinical trial. Such findings need to be con-firmed and advanced in a larger group of pa-tients (Schneeberger et al. 2013).

Facial transplants, along with hand trans-plants, are unique among transplant types inthat they allow for direct visual observation ofrejection episodes. They are also unique in thatthey possess very large amounts of skin, which isone of the most immunoreactive and antigenictissues in the human body (Lee et al. 1991).



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Development of facial transplantation-specificprotocols have adapted primarily from solidorgan transplant protocols. Most centers useinduction therapy with anti-interleukin 2 re-ceptor antibodies (e.g., basiliximab, daclizu-mab) or antithymocyte globulins followed bya maintenance protocol that includes an anti-proliferative agent (mycophenolatemofetil), acalcineurin inhibitor (tacrolimus), and a corti-costeroid (prednisolone) (Siemionow and Oz-turk 2012). Donor origin stem cells have alsobeen used to attempt to induce donor-specifictolerance via the development of a mixed allo-geneic chimerism (Devauchelle et al. 2006; Du-bernard et al. 2007). The goal of maintenancetherapy is to avoid graft rejection, while at thesame time reducing immunosuppression tolimit the adverse events, which include infec-tions and malignancy (van Leeuwen et al. 2010).

Rejection Episodes

One patient in the United States has lost a handallograft as a consequence of arterial intimalhyperplasia on day 275 and one patient inFrance requested amputation following pro-gressive rejection of the skin after stopping im-munosuppression at 29 months (Petruzzo et al.2010). Furthermore, several unconfirmed casesof hand loss have occurred in China. Althoughrejection in hand and face transplantation re-mains incompletely understood at this point,it appears that both the skin and the vascula-ture are important targets for the immune re-sponse in VCA. In some elements, the molecu-lar mechanisms and dynamics of skin rejectionare similar to other inflammatory skin condi-tions. T cells are recruited to the skin via acti-vation of adhesion molecules, cytokines, andchemokines (Hautz et al. 2010b, 2012b). In ad-dition to T-cell recruitment, ectopic lymphoidstructures within the allograft associated withchronic rejection in solid organ transplanta-tion might contribute to the strong alloimmuneresponse toward the skin. In preclinical trials,molecules involved in cell trafficking in the skinhave been successfully targeted to prevent rejec-tion in VCA. In human hand transplantation,episodes of skin rejection have been observed

in the vast majority of cases. Skin rejection wasreversible in all patients compliant with im-munosuppression and graft loss was prevented(Hautz et al. 2010a).

All patients who have .1 year follow-upafter facial transplantation have experienced atleast one episode of acute rejection, which man-ifests as cutaneous changes including skin swell-ing and erythema along with the developmentof nodules and/or papules. Furthermore, sevenpatients have experienced two acute rejectionepisodes and two developed three rejection ep-isodes (Siemionow and Ozturk 2012). Acuterejections have all been confirmed histologicallyvia skin and/or mucosal biopsy. Acute rejectionepisodes were successfully treated using treat-ment algorithms from solid organ rejection in-cluding the use of high-dose parenteral steroidsand the adjustment of oral immunosuppressivetherapy. Unique to facial transplantation is theability to use phototherapy and the topical ap-plication of steroid and tacrolimus creams.

To date, there are also no documented casesof chronic rejection, again likely owing to theshort follow-up, or graft-versus-host disease.In kidney and liver transplantation chronic re-jection may occur anywhere from months toyears posttransplantation and is characterizedby fibrosis of the graft parenchyma (Seetharamet al. 2010). In cardiac transplantation, chronicrejection occurs over the same time course;however, it typically manifests itself as a vascu-lopathy that ultimately leads to loss of the graft(Kalache et al. 2011). As follow-up times in fa-cial and hand allotransplantation are limitedit is unclear yet whether chronic rejection willmanifest with more fibrotic changes to the skinand subcutaneous tissues or with a vasculop-athy of the transplanted vessels. Furthermore,we do not know exactly over what time coursechronic rejection will occur although we wouldexpect it to be similar to that seen in solid organtransplantation.

COMPLICATIONS

A total of five patients have lost their grafts afterhand transplantation. One patient lost his handas a consequence of intimal hyperplasia in the

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arteries of the graft on day 275 (Louisville) andone patient as a result of progressive rejection ofthe skin after stopping immunosuppression at29 months (Lyon) (Kanitakis et al. 2003; Kauf-man et al. 2012). Two hands were lost subse-quent to arterial thrombosis in Wroclaw (Ja-blecki 2011). Furthermore, one hand each wasreamputated after transplantation in Atlantaand Boston (Pomahac et al. 2012a). Graft sur-vival in hand transplantation 14 years after thefirst case is currently 82%.

In one case, a venous thrombosis was treatedby microsurgical revision (Petruzzo et al. 2010).The thrombosis of an ulnar artery, which re-quired thrombectomy, occurred in anothercase. There was also one case in which an arte-riovenous shunt was observed requiring liga-tion. Skin necrosis was observed in four casesand required treatment with skin grafts (Pe-truzzo et al. 2010). A hematoma resulted inwound dehiscence on day 15 after transplanta-tion in one case (Jablecki et al. 2009). In anothercase, a tenolysis for flexor tendon adhesions wasrequired at 14 months (Schuind et al. 2007).Aseptic necrosis of a hip required treatmentwith bilateral arthroplasty in one patient (Pe-truzzo et al. 2010). In one case, Staphylococcusaureus osteomyelitis in the ulna was encoun-tered and treated with antibiotics. CMV infec-tion was reported in a large number of cases.Human papilloma virus infection, herpes sim-plex infection, fungal infections of the skin andmucosa, and a Clostridium difficile enteritiswere reported in a smaller number of patients(Petruzzo et al. 2010). Frequently, transient hy-perglycemia, hypertension, and impaired kid-ney function were observed but reversible withadequate medical treatment (Petruzzo et al.2010). A basal cell carcinoma of the nose wastreated by surgical excision (Landin et al. 2010).

Although psychiatric disorders like depres-sion, fear, or denial of the transplanted hand,may appear especially early after transplanta-tion, the overall adjustment to the new limbhas been very good in most cases (Kumnig etal. 2012). In some patients the allografts werefully integrated in cerebral cortex and body im-age when sensitivity was established. Neverthe-less, a suicide attempt was reported in one pa-

tient (Schuind et al. 2007), whereas the firstrecipient of a hand allograft in the recent eraof hand transplantation requested reamputa-tion when the hand showed signs of progressiverejection after cessation of immunosuppression(Schneeberger et al. 2011).

One significant problem in some cases af-ter hand transplantation was compliance withmedication and the demanding rehabilitationprotocol. Although the existing experience withhand transplantation indicates that noncom-pliance is more common after unilateral thanbilateral hand transplantation, this remains tobe confirmed in a larger series of patients. A de-tailed psychological evaluation and risk assess-ment remains a prerequisite for patients enlistedfor hand transplantation.

In face transplantation there have been nodocumented cases of loss of the allograft second-ary to surgical complications such as arterialor venous thrombosis. One patient did requirereoperation 3 days postoperatively secondary toa venous thrombosis; however, the anastomosiswas revised with salvage of the allograft (Barretet al. 2011). Other documented postoperativesurgical complications including ptosis of theeyelids, ectropion, Stenson’s duct stenosis, andgeneralized wound healing problems have allbeen able to be managed conservatively.

The two most feared complications withimmunosuppressive therapy are infections andmalignancy. All facial transplantation patientsreceived prophylaxis against opportunistic in-fections, which typically consists of coverageagainst herpes simplex (acyclovir), cytomega-lovirus (ganciclovir), and Pneumocystis jero-vici (trimethoprim-sulfamethoxazole). Despitethese measures the majority of patients had atleast one episode of an opportunistic bacterial,viral, or fungal infection including cytomegalo-virus, Epstein–Barr virus, herpes simplex, her-pes zoster, staphylococcal, Pseudomonas, Enter-obacter, and Candida infections (Siemionowand Ozturk 2012). There was one death owingto Pseudomonas infection reported in a patientwho underwent face as well as bilateral handtransplant (Lantieri et al. 2011). A second deathwas reported in the patient of Guo et al. (2008)after being noncompliant with immunosup-



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pression therapy (Siemionow and Ozturk 2012).Malignancy has been already reported despitethe relative infancy of facial transplantation.The first facial transplantation patient devel-oped a cervical carcinoma in situ that was suc-cessfully treated with conization (Petruzzo et al.2012).

OUTLOOK: BASIC AND CLINICAL SCIENCE

Hand and face allotransplantation are demand-ing and challenging operations and especiallyfor face transplantation, mock transplantationsvia cadaveric dissections are recommended be-fore performing the actual operation to ensureoptimal outcomes. Several investigators have re-ported on the use of computerized tomographyand cephalometric analysis to plan potentialoperations (Brown et al. 2012; Caterson et al.2012). The major hurdle for wider range appli-cation of hand and face transplantation, how-ever, remains the reduction or elimination ofthe need for long-term immunosuppressivetreatment. The side effects of immunosuppres-sion hamper the progress in this field as thevariety and severity of side effects negatively im-pact on the risk–benefit balance of such non-lifesaving procedures.

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