- Email: [email protected]
Transplantation of the hand
Transplantation Reviews 19 (2005) 100 – 107 www.elsevier.com/locate/trre
Transplantation of the hand Stefan Schneeberger a
a,T
, Bettina Zelgerb, Marina Ninkovica, Raimund Margreitera,T
Department of General and Transplant Surgery, Innsbruck Medical University, A-6020 Innsbruck, Austria b Department of Pathology, Innsbruck Medical University, A-6020 Innsbruck, Austria
Abstract This review provides an overview of the progress made to date in hand transplantation. Working from published data and our own observations, we outline important aspects in this novel field. We believe that hand transplantation poses a therapeutic option for a select group of patients. D 2005 Elsevier Inc. All rights reserved.
1. Introduction
2. Reaching novel dimensions
Replantation is the predominant surgical treatment after amputation of a digit, hand, forearm, or an arm. Advances in microsurgery have made readaption of a limb or smaller parts such as a finger possible. In many cases, however, either severe tissue injury does not permit sufficient reconstruction of all components or thrombosis/infection upon replantation necessitates reamputation. In such a case, patients suffer from the loss of working ability, social interaction, and body integrity, and from appearance. Prostheses without motor function have improved cosmetic appearance but are of no functional value and interfere with motor imagery. In contrast, myoelectrical prostheses are valuable tools for performing activities but are of very limited use for social interaction because they lack sensitivity. In the same time frame as advances in microsurgery were achieved, progress in immunosuppression has minimized acute rejection and organ loss early after transplantation. The ultimate goal in organ allotransplantation, namely, the induction of tolerance, has, however, not been achieved so far. Nevertheless, recently introduced innovative immunosuppressive protocols appear to provide the opportunity for minimizing long-term immunosuppression [1-5].
In many ways, novel dimensions have been reached with the introduction of composite tissue allotransplantation. Reconstruction and composite tissue allograft (CTA) survival not only of the hand but also of other body compartments seem possible, and further progress in this field is hindered not by surgical expertise but by ethical considerations. Two major differences between hand and organ transplantation, which is widely accepted as a treatment of end-stage organ failure, are the subjects of debate: (1) transplantation of a limb, tongue, larynx, or face is not life saving, nor does it positively influence long-term patient survival; (2) in contrast to organs, a hand or a face is visible to the patient as well as the public including the donor family. Potential consequences were made the subject of a novel by John Irving [6], and, although his scenario is largely unrealistic, ongoing public relations efforts including open discussions are needed to prevent such consequences. In this context, the patients’ point of view and their feelings and attitude toward composite tissue allotransplantation need to be taken into consideration by surgeons, ethicists, and the public. 3. International registry and hand transplant symposiums
T Corresponding authors. Tel.: +43 512 504 22601; fax: +43 512 504 22605. E-mail addresses: [email protected] (S. Schneeberger)8 [email protected] (R. Margreiter). 0955-470X/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.trre.2005.07.001
After the first hand transplantations had been performed between 1998 and 2000, international meetings on composite tissue transplantation were held every year and provided the opportunity to present and discuss advances as well as problems in this field [7-9]. It soon became
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
apparent that graft survival under conventional immunosuppressive treatment would be high. In fact, after transplantation of 24 hands/forearms/digits, the 1- and 2-year graft survival rates were 100%. The founding of the bInternational Registry on Hand and Composite Tissue Transplantation (IRHCTT)Q (www.handregistry.com) in 2002 resulted in the collection, analysis, and comparability of results achieved by institutions on different continents. The IRHCTT website and its reports, together with international meetings, now provide the basis for developing improved guidelines and future clinical protocols for hand transplantation [10]. 4. Ethics Ethical considerations and discussions were often based on the assumption that hand transplantation is a therapeutic option for all patients after hand loss [11-14]. By contrast, all centers actually performing hand transplantation state in publications and, in particular, in discussions at national and international conferences on this topic, that such a procedure is performed only upon careful patient selection [15-20]. Several inclusion as well as exclusion criteria have been defined, and a large number of patients were denied a hand transplant because one or more criteria were not met [19-21]. At our institution, patients requesting a transplant were classified as nontransplantable because of, for example, a neurinoma proximal to the amputation level or loss of hands in a suicide attempt. Most importantly, the first clear inclusion criterion for patient selection is a strong desire by the candidate. Unfortunately, many ethics debates do not take interindividual differences into consideration, but instead, discuss the potential benefit or disadvantage in a nonselected group of patients, for example, single-hand–amputated volunteers (not necessarily requesting a transplant) [11]. Ever since the hand transplant program in the bnew eraQ of immunosuppression was launched, polarization between those in support of and those against hand transplantation has resulted in more or less suggestive conclusions and recommendations than in a scientific evaluation of results. After disapproving initial fears that the transplanted limbs might be irreversibly rejected early after transplantation and that function would be poor, criticism now focuses on longterm function. Again, given scenarios lack proof, and so far, no loss of function has been reported in those patients carrying a hand transplant for more than 5 years. Conclusions regarding justification of hand or other CTA transplantation are thus made on the basis of estimated rather than calculated or documented benefit-to-risk ratios or on evaluation of patients not requesting such a transplant [11-13]. In contrast, when recipients of a hand or forearm were questioned about their well-being and their satisfaction, most patients agreed that their quality of life had profoundly improved [17,18]. Because scoring systems previously used for hand replantation are not efficacious for evaluating patient satisfaction in addition to hand function, new
101
questionnaires have been developed. In the future, the results of the bcomprehensive evaluation systemQ will help provide a better picture of the outcome including a patient’s point of view [22]. At the moment, no conclusive statements can be made, but the actual satisfaction of our patients as well as the reported outcomes of others, together with the lack of evidence for chronic rejection at 6 years after launch of the hand transplant program, advocates continuation of hand transplantation. This review gives an overview of hand transplantation and focuses on actual patient data rather than potential scenarios. Based on the observations made to date, we then outline important aspects to be taken into consideration in this novel field in the future.
5. Patient selection Detailed selection criteria are not available from all centers; however, criteria used at our own institution are similar to those at most other centers: (1) the patient’s request—only highly motivated patients actively requesting a hand transplant can be accepted; (2) amputation at a level distal to the elbow; (3) informed consent—the patient needs to be informed in detail about the functional outcome to be expected after hand transplantation and, more importantly, about the consequences long-term immunosuppression might have on metabolic and organ function, the risk of infection as well as tumor development. The difficulty in predicting long-term outcome needs to be explained; (4) candidates need to be physically fit apart from the injured limb and (5) psychologically stable and able to understand the complexity of such a procedure as confirmed by an independent expert. Patients must be given time to weight the anticipated improvement in quality of life against the potential risk of the transplant.
6. Recipients Since 1998, 18 patients have been selected from several hundred candidates to receive a thumb (n = 1), a single hand (n = 11), a bilateral hand (n = 6), or forearm (n = 2). One of the forearm recipients received all the forearm muscles; however, bone conjunction was completed at a level just distal to the elbow. Transplants were performed at 8 centers on 3 continents. The largest number of patients were transplanted in 2000 (n = 5) and 2001 (n = 4). Between 2002 and 2005, only 4 hand transplants were reported to the registry. Three reasons for the decreasing number of patient are considered particularly relevant: (1) the long-term results of patients transplanted to date are a prerequisite for continuing/starting a hand transplant program; (2) hand transplantation is cost- and labor-intensive and expenses are not covered by medical insurance in many countries; (3) of all the candidates, only a few are bgood candidatesQ who meet the criteria.
102
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
Recipient age was 19 to 52 years (mean, 32), and time since amputation varied between 2 months and 22 years. It is remarkable that only 10 of 18 patients were equipped with prostheses after hand loss. We feel that muscle stimulation induced by a myoelectrical prosthesis is important for muscle and cortex stimulation. It goes without saying that patients had to be free of infection and show no signs of malignancy. More detailed patient characteristics were published very recently and will not be repeated here in detail [10]. It has already been mentioned that detailed informed consent was of utmost importance. 7. Donors Mean donor age was 33 years (range, 16–50 years). Donors were matched with the recipient for blood group, sex, age, bone size, and texture in all instances. Mean HLA antigen mismatch was high [4,8], and 6 patients had a complete mismatch (6/6) [10]. Limited donor availability and a purposely short ischemia time did not permit HLA matching. Although serological testing for cytomegalovirus (CMV) was performed in most donors and recipients, CMV mismatch (donor positive/recipient negative) was not an exclusion criterion because the outstanding importance of virus replication in CTA was recognized only recently [27]. Otherwise, donors had to be negative for HIV, hepatitis B virus, hepatitis C virus, and toxoplasmosis.
motility without jeopardizing the healing process of joined structures. Because bearly protective motionQ after hand replantation has shown favorable results, a similar program was introduced after hand transplantation [24]. Long-term treatment aims at motoric reeducation and sensibility training. Nerve regeneration was assessed from the presence of Tinel’s sign. Diverse programs for rehabilitation have been applied at various centers. The Louisville team applied the same protocol as used after hand replantation [15]. On day 4 after transplantation, an (protected) active range of motion (ROM) exercise was begun. Electrical stimulation of finger flexor and extensor muscles was started at week 2. The protocol aimed to maximize the ROM and strength and was continued for 3 months. The Lyon team emphasized early sensory reeducation and cortical reintegration in addition to controlled motion passive and active exercises and electrostimulation [16,17]. In Innsbruck, sensory reeducation was given high priority, and, therefore, the specific cognitive exercise program described by Perfetti was a cornerstone of the rehabilitation program [18]. A variety of thermoplastic splints were used for graft protection to avoid retraction and facilitate rehabilitation. Occupational therapy focused on sensory stimulation of the hands and forearms as well as on work-related and daily living activities. Electrical stimulation of the thenar and hypothenar muscles and electromyographic biofeedback training were introduced at weeks 3 and 9, respectively.
8. Surgical procedure No standardized protocol was followed by the institutions carrying out hand transplantation, and surgical performance had to be adapted to the level of amputation as well as the exact position and quality of structures in the recipient’s stump. Sixteen transplants were performed at the level of the distal forearm or wrist, which is the optimal level: forearm muscles are of recipient origin and the intact motor function allows early active motion and cortical (re)integration. Intrinsic muscle functions as well as sensitivity recommence later, when nerve regeneration has reached the respective muscles. Cold ischemia time varied between 30 minutes and 13 hours with a mean of 5.3 hours. This is very long when considering that muscles are sensitive to ischemia, and damage such as interstitial edema, microvascular constriction, or damage to the muscle cell membranes results in muscle dysfunction already after 2.5 hours of (warm) ischemia [23]. Although cold flush and preservation with University of Wisconsin (or similar) solutions might limit myocyte damage, short ischemia time is desirable. Why saline solution was used in 2 cases was not explained. 9. Rehabilitation The goal of early rehabilitation is to control swelling and pain, prevent joint stiffness and adhesion, and achieve good
10. Results 10.1. Surgery, healing Provided that anatomical structures proximal to the amputation level are intact, the lack of concomitant injuries and the sufficient length of graft structures made surgery technically easier as compared to hand replantation [17,25,26]. Surgical complications such as AV fistulas, skin necrosis, and arterial thrombosis were observed in some cases (n = 4) but were easily corrected [10]. Among nonsurgical complications, an avascular hip necrosis in one patient was the most severe. One osteomyelitis of the ulnar responded to antibiotics, and treatment of 5 cases of cutaneous mycosis was reported but not further specified. One additional case of cutaneous mycosis observed very recently in one of our own patients responded to local excision and a short course of amphotericin followed by itraconazole (Bonatti H, et al, manuscript in preparation). Cytomegalovirus infection complicated the postoperative course in 5 patients [27]. Virus replication was associated with clinical symptoms (n = 2) and rejection in some cases. In addition, elimination of the virus was difficult and drug toxicity was frequently seen. It was therefore recommended that CMV mismatch between donor and recipient be avoided. Prophylaxis with ValGCVand anti-CMV hyperimmunoglobulin should be mandatory, and an additional reduction of
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
103
been reported whether immunosuppression in patients with no or one rejection episode was higher than in others [15,28]. First rejection episodes responded to steroids, whereas repeated rejections were treated with various regimens including ATG or basiliximab. In one case of a steroid- and ATG-resistant rejection, Campath-1H was given and restored normal skin histology (Fig. 1) [28]. Progressive acute rejection after withdrawal of immunosuppression (noncompliance) prompted lichenlike lesions requiring amputation of the first hand transplant at 2 years and 4 months after transplantation [29]. Although it has been speculated that rejection might have been reversible, treatment with a steroid bolus and an anti-CD25 antibody did not prevent progression of rejection. In numerous publications, it has been stated that conventional immunosuppression, comparable to that used in kidney transplantation, is sufficient for hand transplantation. However, as repeated rejections and rejections resistant to steroids have been observed in some patients, this is probably not true for all patients [28,30 -32]. 10.3. Histological grading of acute rejection in skin biopsies
Fig. 1. Steroid- and ATG-resistant rejection (grade IVa) occurring at day 95 after double-forearm transplantation (A). The maculopapulous lesions are scattered irregularly over the transplant, and biopsies taken at unaffected sites showed normal histology. Rejection responded promptly to Campath-1H; lesions as well as histological signs of rejection disappeared within 2 weeks after treatment (B).
The skin seems to be the major target of rejection. This represents a unique situation in transplantation, where visual inspection permits daily graft monitoring. Even in advanced acute rejection, only a mild mononuclear perivascular infiltrate was found in other tissues [29]. When maculopapulous lesions were investigated by histology of skin biopsy samples, lymphocytic and eosinophilic infiltrates, epidermal lymphocytic interphase reaction, keratinocyte necrosis as well as dermal/epidermal separation were the main features encountered [15-18,28,29,33]. Working from our own observations as well as from published data, a scoring system was developed for rejection of the skin as part of a CTA (Figs. 2 and 3, Table 1) [15-18,28,29,33,34]. Accordingly, lymphocytic and eosinophilic perivascular infiltrates represent a grade I immunoreaction, an interphase reaction in epidermis, or adnexal structures was rated a mild (grade II) and a diffuse infiltrate a sign of a moderate rejection (grade III). Severe rejection is defined as the presence of keratinocyte necrosis with dermal/epidermal separation (grade IV, Fig. 3). The established grading system enables comparison of graft rejection severity at different centers. It does not
immunosuppression should be initiated. Foscarnet and cidofovir represent a third-line therapeutic option. 10.2. Acute rejection Immunosuppressive protocols included induction therapy with anti–thymocyte globulin (ATG) or basiliximab in all but 2 patients. Otherwise, standard IS protocols using tacrolimus, steroids, and mycophenolate mofetil were applied [10]. An average of 1.4 rejection episodes per patient was encountered, 6 patients did not experience any rejection, and only 3 patients had more than 2 rejection episodes. It has not
Fig. 2. Normal skin histology after hand transplantation.
104
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
Table 1 Grading for determination of rejection in skin biopsies of transplanted hands Description
Grade
Histology
Minimal rejection
Grade I
Mild rejection
Grade II
Moderate rejection
Grade III
Severe rejection
Grade IVa
Perivascular lymphocytic and eosinophilic infiltrates Additional interphase reaction in epidermis and/or adnexal structures Diffuse lymphocytic infiltration of epidermis and dermis Necrosis of single keratinocytes and focal dermal-epidermal separation Necrosis and loss of the epidermis
Grade IVb
include features of chronic rejection because this has not been observed so far. Importantly, patterns of skin lesion were heterogeneously scattered over both hands/forearms in all rejection episodes observed independently of severity (Fig. 1). Biopsies taken near the lesions but not exactly from the affected areas showed normal histology. Hence, the exact site of skin sampling is of utmost importance. Morphological changes in severe CTA rejection included destructive processes such as cell death and desquamation of the epidermis, although even advanced degrees of skin lesion (grade IV) seem to be reversible. 10.4. Chimerism Initial expectations that vascularized bone marrow might induce chimerism or donor hyporesponsiveness after hand transplantation were not realized. However, Langerhans’ cells of recipient origin were found in the graft skin early (day 77) after transplantation [18,35,36]. This observation gave rise to the idea that other cell types of the graft could also be replaced by recipient cells in the long term. 10.5. Function Extrinsic muscle function was observed early after transplantation in most patients. The duration of time needed to reach optimal function has not been reported. In particular, reactivation of intrinsic hand muscles occurs late (4 months to 5 years) [10]. In our own patients, motor recovery continued throughout the first 2 years after transplantation and then remained stable (Schneeberger S, et al, manuscript in preparation). We therefore decided to continue intense physiotherapy for 2 years, and to a much lesser extent, thereafter. Grip strength varies from less than 0.5 to more than 10 kg, and discriminative sensation (Highet Scale as modified by Dellon) ranged from grade S2 to grade S4 [10]. Active ROM was published for only a few patients, the overall average ROM of our first hand transplant recipient being 60.1% (Fig. 4). Hand function in most patients is sufficient to perform activities of daily life such as brushing teeth, combing hair, and attending to personal hygiene. More advanced skills such as needed to write, turn a page, use a computer or a cellular phone, eat with a knife and fork, play cards, pick up
Fig. 3. Grading of skin rejection in hand transplants. Grade I: perivascular infiltrates (lymphocytes and eosinophils); grade II: interphase reaction (dermis/epidermis) and/or adnexal structures in addition to perivascular infiltrates; grade III: cellular infiltrate in dermis and epidermis; grade IVa: necrosis of single keratinocytes together with focal dermal-epidermal separation; grade IVb: necrosis and loss of epidermis.
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
105
Fig. 4. Function of extrinsic and intrinsic muscles after double-hand transplantation.
small objects, and dress oneself were achieved by some patients. It is important to note that all patients experienced recovery of protective sensation including thermal discrimination and sensitivity to pain. 10.6. Cortical reorganization Investigation of motor cortex activity demonstrated reversibility of cortical reorganization after hand amputation and hand transplantation [37,38]. Areas representing unaffected muscles were known to expand after amputation. Functional magnetic resonance imaging mapping after single- as well as double-hand transplantation demonstrated recognition and cortical reintegration of the hand, suggesting that novel peripheral inputs allow global remodeling of the sensomotoric cortex. The shown plasticity of the brain might also be relevant after single nondominant hand amputation and transplantation: after the loss of a dominant hand, enhanced stimulation of the nondominant side might result in enhanced skillfulness or sensomotoric cortex activity. The superiority of a dominant hand might therefore be of minor relevance in such a situation. Because the possibility of an advantage (or disadvantage) of dominant vs nondominant hand transplantation has not yet been investigated, it remains unclear whether the loss of a nondominant hand is a poorer indication for transplantation than the loss of a dominant hand. 10.7. The Innsbruck experience Our own experience is drawn from one patient who received a bilateral hand and one patient who underwent bilateral forearm transplantation. In addition, participation in the IRHCTT allowed interaction and comparison with all other centers performing hand transplantations. In our opinion, some aspects and strategies are particularly relevant when striving to achieve good results after hand transplantation: Cold ischemia time was kept short, and performance of donor and recipient operation in adjacent theatres allowed cold ischemia time to be limited to 150/170 and 155/153 minutes in the first and second recipient, respectively [18,28]. The immunosuppressive protocol included induction therapy with ATG to prevent early rejection and Tacrolimus during the first 2 years after transplantation to take advantage of the beneficial effect of Tacrolimus on nerve
regeneration. For long-term immunosuppression, a combination of mycophenolate mofetil together with rapamycin was introduced with the aim of preventing chronic rejection. We believe that rehabilitation should be intensive and long lasting. Our intensive rehabilitation program included sensory reeducation. The specific cognitive exercise program after Perfetti was introduced to achieve the patients reprogram a patient’s motor action. It accounted for more than 80% of rehabilitation. Hand transplantation is teamwork; surgeons, neurologists, specialists in physical medicine, physical, and occupational therapists discussed the patient’s clinical course at regular intervals and whenever clinically indicated. 10.8. Is hand transplantation justified? Hand transplantation has grown beyond the state of bearly experiments,Q and many questions raised by the first cases can now be answered: (1) Immunosuppression similar to that used in heart, pancreas, or kidney transplantation is sufficient to prevent early graft loss in most cases; (2) the incidence of malignancy seems to be low as no malignancy has been observed so far; (3) with regard to infections, CMV plays a dominant role, and CMV mismatch transplantation should therefore be avoided. Cutaneous mycosis (n = 6) has been observed in a relatively large number of grafts; [4] chronic rejection does not occur at an early stage. Many doubts have been redressed, but the question whether hand transplantation is justified and worth the enormous effort can nevertheless only be answered on an individual basis. The final judgment can be made only by the patient, and we thus feel it should primarily be the patient’s decision to undergo this type of transplantation! So far, 2 transplanted hands have been lost, one of which was in the first patient who received a hand in the new era of hand transplantation; this, therefore, gave immediate rise to speculations that more hands could be rejected and that hand transplantation should be returned to the research lab [36]. Unfortunately, the circumstances under which these 2 CTAs were lost remain somewhat unclear: the first patient was transplanted in Lyon in 1998 but stopped taking immunosuppressive drugs for an unknown time before progressive acute rejection occurred and he requested amputation [29]. It remains unclear whether rejection might have been reversible. The very first report on this case stated that the
106
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
48-year-old businessman refused prostheses before transplantation and quit physiotherapy when he left the hospital at day 108 after transplantation to btravel the worldQ instead of continuing physiotherapy under close observation. Assessment of the clinical course in this patient would therefore seem to be difficult and patient selection somewhat questionable [16,29,39,40]. In addition to noncompliance, neuroma formation and degeneration proximal to the amputation level were reported and may have contributed to the unsatisfactory outcome [16]. Precautions must be taken to avoid such experiences in future, and patient consent as well as completion of rehabilitation and regular outpatient controls should be mandatory. Otherwise, such a cost- and labor-intensive procedure is not justified. A psychological investigation protocol was proposed in 2001 and might help better define the suitability of patients requesting a hand transplantation [41]. In the second case, a severe bskin inflammationQ resistant to ballQ treatment resulted in amputation of the hand at 3 years posttransplantation [10]. No details of this patient were published, and the underlying mechanism can only be speculated. It seems unlikely, however, that any unspecific skin inflammation other than rejection or infection would occur after hand transplantation. This case further underlines the importance of detailed investigation and presentation of the data of the limited number of patients who received a CTA. Tolerance induction has been proposed as a prerequisite for hand transplantation, but it is unrealistic that this will be routinely achieved in the near future. Experimental protocols are either not applicable to the clinical situation, not successful in humans, or bear the risk of a graft-vs-host reaction. However, recent developments in immunosuppression, in particular, the introduction of Campath-1H, might reduce the number and/or severity of acute rejections after hand transplantation [1-4]. Recent studies demonstrate a reduction in the number of acute rejections after kidney transplantation and allow for, for example, low-dose calcineurin inhibitor maintenance therapy [2,4]. Such a regimen is expected to reduce side-effects and tumor probability and might result in partial tolerance of the graft. However, how these regimens will influence composite tissue allotransplantation can only be speculated at the moment. On the basis of early experience, we believe that hand transplantation is a valuable therapeutic option for a select group of patients. Acknowledgments This manuscript is based in part on data from the International Registry on Hand and Composite Tissue Transplantation (IRHCTT). The authors thank all participant teams for their data contribution. Participants in the IRHCTT: Erasme University Hospital, Brussels, Belgium (C Van Holder, F Schuind); Hospices Civil de Lyon, Lyon, France (JM Dubernard, P Petruzzo); University of Louis-
ville, Louisville, Ky (WC Breidenbach); Nanfang Hospital, The First Military Medical University, Guangzhou, China (GX Pei); The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (J Zhao); The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjian, China (X Zhang); Innsbruck Medical University, Innsbruck, Austria (R Margreiter, S Schneeberger); Universita di Milano—Bicocca, Monza, Italy (M Lanzetta, S Luccina). References [1] Reyes J, Mazariegos GV, Abu-Elmagd K, et al. Intestinal transplantation under Tacrolimus monotherapy after perioperative lymphoid depletion with rabbit anti–thymocyte globulin (Thymoglobulin). Am J Transplant 2005;5:1430. [2] Shapiro R, Basu A, Tan H, et al. Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with Thymoglobulin or Campath. J Am Coll Surg 2005;200:505. [3] Oike F, Yokoi A, Nishimura E, et al. Complete withdrawal of immunosuppression in living donor liver transplantation. Transplant Proc 2002;34:1521. [4] Watson CJ, Bradley JA, Friend PJ, et al. Alemtuzumab (CAMPATH 1H) Induction therapy in cadaveric kidney transplantation-efficacy and safety at five years. Am J Transplant 2005;5:1347. [5] Starzl TE. Back to the future. Transplantation 2005;79:1009. [6] Irving J. The fourth hand. New York (NY)7 Random House Trade; 2001. [7] Barker JH, Breidenbach WC, Hewitt CW. Second international symposium on composite tissue allotransplantation. Introduction. Microsurgery 2000;20:359. [8] Barker JH, Francois CG, Frank JM, et al. Composite tissue allotransplantation. Transplantation 2002;73:832. [9] Francois CG, Breidenbach WC, Maldonado C, et al. Hand transplantation: comparisons and observations of the first four clinical cases. Microsurgery 2000;20:360. [10] Lanzetta M, Petruzzo P, Margreiter R, et al. The International Registry on Hand and Composite Tissue Transplantation. Transplantation 2005;79:1210. [11] McCabe S, Rodocker G, Julliard K, et al. Using decision analysis to aid in the introduction of upper extremity transplantation. Transplant Proc 1998;30:2783. [12] Lees VC, McCabe SJ. The rationale for hand transplantation. Transplantation 2002;74:749. [13] Jones NF. Concerns about human hand transplantation in the 21st century. J Hand Surg [Am] 2002;27:771. [14] Dickenson D, Widdershoven G. Ethical issues in limb transplants. Bioethics 2001;15:110. [15] Jones JW, Gruber SA, Barker JH, et al. Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team. N Engl J Med 2000;343:468. [16] Dubernard JM, Owen E, Herzberg G, et al. Human hand allograft: report on first 6 months. Lancet 1999;353:1315. [17] Dubernard JM, Petruzzo P, Lanzetta M, et al. Functional results of the first human double-hand transplantation. Ann Surg 2003;238:128. [18] Margreiter R, Brandacher G, Ninkovic M, et al. A double-hand transplant can be worth the effort! Transplantation 2002;74:85. [19] Petruzzo P, Badet L, Lanzetta M, et al. Concerns on clinical application of composite tissue allotransplantation. Acta Chir Belg 2004;104:266. [20] Lanzetta M, Petruzzo P, Vitale G, et al. Human hand transplantation: what have we learned? Transplant Proc 2004;36:664. [21] Germann G. Bilateral hand transplantation—indication and rationale. J Hand Surg [Br] 2001;26:521.
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107 [22] Dubernard JM. Composite tissue allografts: a challenge for transplantologists. Am J Transplant 2005;5:1580. [23] Nanobashvili J, Neumayer C, Fugl A, et al. Ischemia/reperfusion injury of skeletal muscle: plasma taurine as a measure of tissue damage. Surgery 2003;133:91. [24] Scheker LR, Hodges A. Brace and rehabilitation after replantation and revascularization. Hand Clin 2001;17:473. [25] Petit F, Minns AB, Dubernard JM, et al. Composite tissue allotransplantation and reconstructive surgery: first clinical applications. Ann Surg 2003;237:19. [26] Kvernmo HD, Gorantla VS, Gonzalez RN, et al. Hand transplantation. A future clinical option? Acta Orthop Scand 2005;76:14. [27] Schneeberger S, Lucchina S, Lanzetta M et al. CMV-related complications in human hand transplantation. Transplantation [in press]. [28] Schneeberger S, Kreczy A, Brandacher G, et al. Steroid- and ATGresistant rejection after double forearm transplantation responds to Campath-1H. Am J Transplant 2004;4:1372. [29] Kanitakis J, Jullien D, Petruzzo P, et al. Clinicopathologic features of graft rejection of the first human hand allograft. Transplantation 2003;76:688. [30] Petruzzo P, Lefrancois N, Kanitakis J, et al. Immunosuppression in composite tissue allografts. Transplant Proc 2001;33:2398. [31] Petruzzo P, Revillard JP, Kanitakis J, et al. First human double hand transplantation: efficacy of a conventional immunosuppressive protocol. Clin Transplant 2003;17:455.
107
[32] Dubernard JM, Burloux G, Giraux P, et al. Three lessons learned from the first double hand transplantation. Bull Acad Natl Med 2002;186:1051 [discussion 1062]. [33] Kanitakis J, Jullien D, Nicolas JF, et al. Sequential histological and immunohistochemical study of the skin of the first human hand allograft. Transplantation 2000;69:1380. [34] Levi DM, Tzakis AG, Kato T, et al. Transplantation of the abdominal wall. Lancet 2003;361:2173. [35] Granger DK, Briedenbach WC, Pidwell DJ, et al. Lack of donor hyporesponsiveness and donor chimerism after clinical transplantation of the hand. Transplantation 2002;74:1624. [36] Kanitakis J, Jullien D, Claudy A, et al. Microchimerism in a human hand allograft. Lancet 1999;354:1820. [37] Giraux P, Sirigu A, Schneider F, et al. Cortical reorganization in motor cortex after graft of both hands. Nat Neurosci 2001;4:691. [38] Neugroschl C, Denolin V, Schuind F, et al. Functional MRI activation of somatosensory and motor cortices in a hand-grafted patient with early clinical sensorimotor recovery. Eur Radiol 2005 [Electronic publication ahead of print]. [39] Hettiaratchy S, Butler PE, Lee WP. Lessons from hand transplantations. Lancet 2001;357:494. [40] Foucher G. Prospects for hand transplantation. Lancet 1999;353:1286. [41] Carta I, Convertino O, Cornaggia CM. Psychological investigation protocol of candidates for hand transplantation. Transplant Proc 2001;33:621.
Transplantation of the hand Stefan Schneeberger a
a,T
, Bettina Zelgerb, Marina Ninkovica, Raimund Margreitera,T
Department of General and Transplant Surgery, Innsbruck Medical University, A-6020 Innsbruck, Austria b Department of Pathology, Innsbruck Medical University, A-6020 Innsbruck, Austria
Abstract This review provides an overview of the progress made to date in hand transplantation. Working from published data and our own observations, we outline important aspects in this novel field. We believe that hand transplantation poses a therapeutic option for a select group of patients. D 2005 Elsevier Inc. All rights reserved.
1. Introduction
2. Reaching novel dimensions
Replantation is the predominant surgical treatment after amputation of a digit, hand, forearm, or an arm. Advances in microsurgery have made readaption of a limb or smaller parts such as a finger possible. In many cases, however, either severe tissue injury does not permit sufficient reconstruction of all components or thrombosis/infection upon replantation necessitates reamputation. In such a case, patients suffer from the loss of working ability, social interaction, and body integrity, and from appearance. Prostheses without motor function have improved cosmetic appearance but are of no functional value and interfere with motor imagery. In contrast, myoelectrical prostheses are valuable tools for performing activities but are of very limited use for social interaction because they lack sensitivity. In the same time frame as advances in microsurgery were achieved, progress in immunosuppression has minimized acute rejection and organ loss early after transplantation. The ultimate goal in organ allotransplantation, namely, the induction of tolerance, has, however, not been achieved so far. Nevertheless, recently introduced innovative immunosuppressive protocols appear to provide the opportunity for minimizing long-term immunosuppression [1-5].
In many ways, novel dimensions have been reached with the introduction of composite tissue allotransplantation. Reconstruction and composite tissue allograft (CTA) survival not only of the hand but also of other body compartments seem possible, and further progress in this field is hindered not by surgical expertise but by ethical considerations. Two major differences between hand and organ transplantation, which is widely accepted as a treatment of end-stage organ failure, are the subjects of debate: (1) transplantation of a limb, tongue, larynx, or face is not life saving, nor does it positively influence long-term patient survival; (2) in contrast to organs, a hand or a face is visible to the patient as well as the public including the donor family. Potential consequences were made the subject of a novel by John Irving [6], and, although his scenario is largely unrealistic, ongoing public relations efforts including open discussions are needed to prevent such consequences. In this context, the patients’ point of view and their feelings and attitude toward composite tissue allotransplantation need to be taken into consideration by surgeons, ethicists, and the public. 3. International registry and hand transplant symposiums
T Corresponding authors. Tel.: +43 512 504 22601; fax: +43 512 504 22605. E-mail addresses: [email protected] (S. Schneeberger)8 [email protected] (R. Margreiter). 0955-470X/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.trre.2005.07.001
After the first hand transplantations had been performed between 1998 and 2000, international meetings on composite tissue transplantation were held every year and provided the opportunity to present and discuss advances as well as problems in this field [7-9]. It soon became
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
apparent that graft survival under conventional immunosuppressive treatment would be high. In fact, after transplantation of 24 hands/forearms/digits, the 1- and 2-year graft survival rates were 100%. The founding of the bInternational Registry on Hand and Composite Tissue Transplantation (IRHCTT)Q (www.handregistry.com) in 2002 resulted in the collection, analysis, and comparability of results achieved by institutions on different continents. The IRHCTT website and its reports, together with international meetings, now provide the basis for developing improved guidelines and future clinical protocols for hand transplantation [10]. 4. Ethics Ethical considerations and discussions were often based on the assumption that hand transplantation is a therapeutic option for all patients after hand loss [11-14]. By contrast, all centers actually performing hand transplantation state in publications and, in particular, in discussions at national and international conferences on this topic, that such a procedure is performed only upon careful patient selection [15-20]. Several inclusion as well as exclusion criteria have been defined, and a large number of patients were denied a hand transplant because one or more criteria were not met [19-21]. At our institution, patients requesting a transplant were classified as nontransplantable because of, for example, a neurinoma proximal to the amputation level or loss of hands in a suicide attempt. Most importantly, the first clear inclusion criterion for patient selection is a strong desire by the candidate. Unfortunately, many ethics debates do not take interindividual differences into consideration, but instead, discuss the potential benefit or disadvantage in a nonselected group of patients, for example, single-hand–amputated volunteers (not necessarily requesting a transplant) [11]. Ever since the hand transplant program in the bnew eraQ of immunosuppression was launched, polarization between those in support of and those against hand transplantation has resulted in more or less suggestive conclusions and recommendations than in a scientific evaluation of results. After disapproving initial fears that the transplanted limbs might be irreversibly rejected early after transplantation and that function would be poor, criticism now focuses on longterm function. Again, given scenarios lack proof, and so far, no loss of function has been reported in those patients carrying a hand transplant for more than 5 years. Conclusions regarding justification of hand or other CTA transplantation are thus made on the basis of estimated rather than calculated or documented benefit-to-risk ratios or on evaluation of patients not requesting such a transplant [11-13]. In contrast, when recipients of a hand or forearm were questioned about their well-being and their satisfaction, most patients agreed that their quality of life had profoundly improved [17,18]. Because scoring systems previously used for hand replantation are not efficacious for evaluating patient satisfaction in addition to hand function, new
101
questionnaires have been developed. In the future, the results of the bcomprehensive evaluation systemQ will help provide a better picture of the outcome including a patient’s point of view [22]. At the moment, no conclusive statements can be made, but the actual satisfaction of our patients as well as the reported outcomes of others, together with the lack of evidence for chronic rejection at 6 years after launch of the hand transplant program, advocates continuation of hand transplantation. This review gives an overview of hand transplantation and focuses on actual patient data rather than potential scenarios. Based on the observations made to date, we then outline important aspects to be taken into consideration in this novel field in the future.
5. Patient selection Detailed selection criteria are not available from all centers; however, criteria used at our own institution are similar to those at most other centers: (1) the patient’s request—only highly motivated patients actively requesting a hand transplant can be accepted; (2) amputation at a level distal to the elbow; (3) informed consent—the patient needs to be informed in detail about the functional outcome to be expected after hand transplantation and, more importantly, about the consequences long-term immunosuppression might have on metabolic and organ function, the risk of infection as well as tumor development. The difficulty in predicting long-term outcome needs to be explained; (4) candidates need to be physically fit apart from the injured limb and (5) psychologically stable and able to understand the complexity of such a procedure as confirmed by an independent expert. Patients must be given time to weight the anticipated improvement in quality of life against the potential risk of the transplant.
6. Recipients Since 1998, 18 patients have been selected from several hundred candidates to receive a thumb (n = 1), a single hand (n = 11), a bilateral hand (n = 6), or forearm (n = 2). One of the forearm recipients received all the forearm muscles; however, bone conjunction was completed at a level just distal to the elbow. Transplants were performed at 8 centers on 3 continents. The largest number of patients were transplanted in 2000 (n = 5) and 2001 (n = 4). Between 2002 and 2005, only 4 hand transplants were reported to the registry. Three reasons for the decreasing number of patient are considered particularly relevant: (1) the long-term results of patients transplanted to date are a prerequisite for continuing/starting a hand transplant program; (2) hand transplantation is cost- and labor-intensive and expenses are not covered by medical insurance in many countries; (3) of all the candidates, only a few are bgood candidatesQ who meet the criteria.
102
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
Recipient age was 19 to 52 years (mean, 32), and time since amputation varied between 2 months and 22 years. It is remarkable that only 10 of 18 patients were equipped with prostheses after hand loss. We feel that muscle stimulation induced by a myoelectrical prosthesis is important for muscle and cortex stimulation. It goes without saying that patients had to be free of infection and show no signs of malignancy. More detailed patient characteristics were published very recently and will not be repeated here in detail [10]. It has already been mentioned that detailed informed consent was of utmost importance. 7. Donors Mean donor age was 33 years (range, 16–50 years). Donors were matched with the recipient for blood group, sex, age, bone size, and texture in all instances. Mean HLA antigen mismatch was high [4,8], and 6 patients had a complete mismatch (6/6) [10]. Limited donor availability and a purposely short ischemia time did not permit HLA matching. Although serological testing for cytomegalovirus (CMV) was performed in most donors and recipients, CMV mismatch (donor positive/recipient negative) was not an exclusion criterion because the outstanding importance of virus replication in CTA was recognized only recently [27]. Otherwise, donors had to be negative for HIV, hepatitis B virus, hepatitis C virus, and toxoplasmosis.
motility without jeopardizing the healing process of joined structures. Because bearly protective motionQ after hand replantation has shown favorable results, a similar program was introduced after hand transplantation [24]. Long-term treatment aims at motoric reeducation and sensibility training. Nerve regeneration was assessed from the presence of Tinel’s sign. Diverse programs for rehabilitation have been applied at various centers. The Louisville team applied the same protocol as used after hand replantation [15]. On day 4 after transplantation, an (protected) active range of motion (ROM) exercise was begun. Electrical stimulation of finger flexor and extensor muscles was started at week 2. The protocol aimed to maximize the ROM and strength and was continued for 3 months. The Lyon team emphasized early sensory reeducation and cortical reintegration in addition to controlled motion passive and active exercises and electrostimulation [16,17]. In Innsbruck, sensory reeducation was given high priority, and, therefore, the specific cognitive exercise program described by Perfetti was a cornerstone of the rehabilitation program [18]. A variety of thermoplastic splints were used for graft protection to avoid retraction and facilitate rehabilitation. Occupational therapy focused on sensory stimulation of the hands and forearms as well as on work-related and daily living activities. Electrical stimulation of the thenar and hypothenar muscles and electromyographic biofeedback training were introduced at weeks 3 and 9, respectively.
8. Surgical procedure No standardized protocol was followed by the institutions carrying out hand transplantation, and surgical performance had to be adapted to the level of amputation as well as the exact position and quality of structures in the recipient’s stump. Sixteen transplants were performed at the level of the distal forearm or wrist, which is the optimal level: forearm muscles are of recipient origin and the intact motor function allows early active motion and cortical (re)integration. Intrinsic muscle functions as well as sensitivity recommence later, when nerve regeneration has reached the respective muscles. Cold ischemia time varied between 30 minutes and 13 hours with a mean of 5.3 hours. This is very long when considering that muscles are sensitive to ischemia, and damage such as interstitial edema, microvascular constriction, or damage to the muscle cell membranes results in muscle dysfunction already after 2.5 hours of (warm) ischemia [23]. Although cold flush and preservation with University of Wisconsin (or similar) solutions might limit myocyte damage, short ischemia time is desirable. Why saline solution was used in 2 cases was not explained. 9. Rehabilitation The goal of early rehabilitation is to control swelling and pain, prevent joint stiffness and adhesion, and achieve good
10. Results 10.1. Surgery, healing Provided that anatomical structures proximal to the amputation level are intact, the lack of concomitant injuries and the sufficient length of graft structures made surgery technically easier as compared to hand replantation [17,25,26]. Surgical complications such as AV fistulas, skin necrosis, and arterial thrombosis were observed in some cases (n = 4) but were easily corrected [10]. Among nonsurgical complications, an avascular hip necrosis in one patient was the most severe. One osteomyelitis of the ulnar responded to antibiotics, and treatment of 5 cases of cutaneous mycosis was reported but not further specified. One additional case of cutaneous mycosis observed very recently in one of our own patients responded to local excision and a short course of amphotericin followed by itraconazole (Bonatti H, et al, manuscript in preparation). Cytomegalovirus infection complicated the postoperative course in 5 patients [27]. Virus replication was associated with clinical symptoms (n = 2) and rejection in some cases. In addition, elimination of the virus was difficult and drug toxicity was frequently seen. It was therefore recommended that CMV mismatch between donor and recipient be avoided. Prophylaxis with ValGCVand anti-CMV hyperimmunoglobulin should be mandatory, and an additional reduction of
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
103
been reported whether immunosuppression in patients with no or one rejection episode was higher than in others [15,28]. First rejection episodes responded to steroids, whereas repeated rejections were treated with various regimens including ATG or basiliximab. In one case of a steroid- and ATG-resistant rejection, Campath-1H was given and restored normal skin histology (Fig. 1) [28]. Progressive acute rejection after withdrawal of immunosuppression (noncompliance) prompted lichenlike lesions requiring amputation of the first hand transplant at 2 years and 4 months after transplantation [29]. Although it has been speculated that rejection might have been reversible, treatment with a steroid bolus and an anti-CD25 antibody did not prevent progression of rejection. In numerous publications, it has been stated that conventional immunosuppression, comparable to that used in kidney transplantation, is sufficient for hand transplantation. However, as repeated rejections and rejections resistant to steroids have been observed in some patients, this is probably not true for all patients [28,30 -32]. 10.3. Histological grading of acute rejection in skin biopsies
Fig. 1. Steroid- and ATG-resistant rejection (grade IVa) occurring at day 95 after double-forearm transplantation (A). The maculopapulous lesions are scattered irregularly over the transplant, and biopsies taken at unaffected sites showed normal histology. Rejection responded promptly to Campath-1H; lesions as well as histological signs of rejection disappeared within 2 weeks after treatment (B).
The skin seems to be the major target of rejection. This represents a unique situation in transplantation, where visual inspection permits daily graft monitoring. Even in advanced acute rejection, only a mild mononuclear perivascular infiltrate was found in other tissues [29]. When maculopapulous lesions were investigated by histology of skin biopsy samples, lymphocytic and eosinophilic infiltrates, epidermal lymphocytic interphase reaction, keratinocyte necrosis as well as dermal/epidermal separation were the main features encountered [15-18,28,29,33]. Working from our own observations as well as from published data, a scoring system was developed for rejection of the skin as part of a CTA (Figs. 2 and 3, Table 1) [15-18,28,29,33,34]. Accordingly, lymphocytic and eosinophilic perivascular infiltrates represent a grade I immunoreaction, an interphase reaction in epidermis, or adnexal structures was rated a mild (grade II) and a diffuse infiltrate a sign of a moderate rejection (grade III). Severe rejection is defined as the presence of keratinocyte necrosis with dermal/epidermal separation (grade IV, Fig. 3). The established grading system enables comparison of graft rejection severity at different centers. It does not
immunosuppression should be initiated. Foscarnet and cidofovir represent a third-line therapeutic option. 10.2. Acute rejection Immunosuppressive protocols included induction therapy with anti–thymocyte globulin (ATG) or basiliximab in all but 2 patients. Otherwise, standard IS protocols using tacrolimus, steroids, and mycophenolate mofetil were applied [10]. An average of 1.4 rejection episodes per patient was encountered, 6 patients did not experience any rejection, and only 3 patients had more than 2 rejection episodes. It has not
Fig. 2. Normal skin histology after hand transplantation.
104
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
Table 1 Grading for determination of rejection in skin biopsies of transplanted hands Description
Grade
Histology
Minimal rejection
Grade I
Mild rejection
Grade II
Moderate rejection
Grade III
Severe rejection
Grade IVa
Perivascular lymphocytic and eosinophilic infiltrates Additional interphase reaction in epidermis and/or adnexal structures Diffuse lymphocytic infiltration of epidermis and dermis Necrosis of single keratinocytes and focal dermal-epidermal separation Necrosis and loss of the epidermis
Grade IVb
include features of chronic rejection because this has not been observed so far. Importantly, patterns of skin lesion were heterogeneously scattered over both hands/forearms in all rejection episodes observed independently of severity (Fig. 1). Biopsies taken near the lesions but not exactly from the affected areas showed normal histology. Hence, the exact site of skin sampling is of utmost importance. Morphological changes in severe CTA rejection included destructive processes such as cell death and desquamation of the epidermis, although even advanced degrees of skin lesion (grade IV) seem to be reversible. 10.4. Chimerism Initial expectations that vascularized bone marrow might induce chimerism or donor hyporesponsiveness after hand transplantation were not realized. However, Langerhans’ cells of recipient origin were found in the graft skin early (day 77) after transplantation [18,35,36]. This observation gave rise to the idea that other cell types of the graft could also be replaced by recipient cells in the long term. 10.5. Function Extrinsic muscle function was observed early after transplantation in most patients. The duration of time needed to reach optimal function has not been reported. In particular, reactivation of intrinsic hand muscles occurs late (4 months to 5 years) [10]. In our own patients, motor recovery continued throughout the first 2 years after transplantation and then remained stable (Schneeberger S, et al, manuscript in preparation). We therefore decided to continue intense physiotherapy for 2 years, and to a much lesser extent, thereafter. Grip strength varies from less than 0.5 to more than 10 kg, and discriminative sensation (Highet Scale as modified by Dellon) ranged from grade S2 to grade S4 [10]. Active ROM was published for only a few patients, the overall average ROM of our first hand transplant recipient being 60.1% (Fig. 4). Hand function in most patients is sufficient to perform activities of daily life such as brushing teeth, combing hair, and attending to personal hygiene. More advanced skills such as needed to write, turn a page, use a computer or a cellular phone, eat with a knife and fork, play cards, pick up
Fig. 3. Grading of skin rejection in hand transplants. Grade I: perivascular infiltrates (lymphocytes and eosinophils); grade II: interphase reaction (dermis/epidermis) and/or adnexal structures in addition to perivascular infiltrates; grade III: cellular infiltrate in dermis and epidermis; grade IVa: necrosis of single keratinocytes together with focal dermal-epidermal separation; grade IVb: necrosis and loss of epidermis.
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
105
Fig. 4. Function of extrinsic and intrinsic muscles after double-hand transplantation.
small objects, and dress oneself were achieved by some patients. It is important to note that all patients experienced recovery of protective sensation including thermal discrimination and sensitivity to pain. 10.6. Cortical reorganization Investigation of motor cortex activity demonstrated reversibility of cortical reorganization after hand amputation and hand transplantation [37,38]. Areas representing unaffected muscles were known to expand after amputation. Functional magnetic resonance imaging mapping after single- as well as double-hand transplantation demonstrated recognition and cortical reintegration of the hand, suggesting that novel peripheral inputs allow global remodeling of the sensomotoric cortex. The shown plasticity of the brain might also be relevant after single nondominant hand amputation and transplantation: after the loss of a dominant hand, enhanced stimulation of the nondominant side might result in enhanced skillfulness or sensomotoric cortex activity. The superiority of a dominant hand might therefore be of minor relevance in such a situation. Because the possibility of an advantage (or disadvantage) of dominant vs nondominant hand transplantation has not yet been investigated, it remains unclear whether the loss of a nondominant hand is a poorer indication for transplantation than the loss of a dominant hand. 10.7. The Innsbruck experience Our own experience is drawn from one patient who received a bilateral hand and one patient who underwent bilateral forearm transplantation. In addition, participation in the IRHCTT allowed interaction and comparison with all other centers performing hand transplantations. In our opinion, some aspects and strategies are particularly relevant when striving to achieve good results after hand transplantation: Cold ischemia time was kept short, and performance of donor and recipient operation in adjacent theatres allowed cold ischemia time to be limited to 150/170 and 155/153 minutes in the first and second recipient, respectively [18,28]. The immunosuppressive protocol included induction therapy with ATG to prevent early rejection and Tacrolimus during the first 2 years after transplantation to take advantage of the beneficial effect of Tacrolimus on nerve
regeneration. For long-term immunosuppression, a combination of mycophenolate mofetil together with rapamycin was introduced with the aim of preventing chronic rejection. We believe that rehabilitation should be intensive and long lasting. Our intensive rehabilitation program included sensory reeducation. The specific cognitive exercise program after Perfetti was introduced to achieve the patients reprogram a patient’s motor action. It accounted for more than 80% of rehabilitation. Hand transplantation is teamwork; surgeons, neurologists, specialists in physical medicine, physical, and occupational therapists discussed the patient’s clinical course at regular intervals and whenever clinically indicated. 10.8. Is hand transplantation justified? Hand transplantation has grown beyond the state of bearly experiments,Q and many questions raised by the first cases can now be answered: (1) Immunosuppression similar to that used in heart, pancreas, or kidney transplantation is sufficient to prevent early graft loss in most cases; (2) the incidence of malignancy seems to be low as no malignancy has been observed so far; (3) with regard to infections, CMV plays a dominant role, and CMV mismatch transplantation should therefore be avoided. Cutaneous mycosis (n = 6) has been observed in a relatively large number of grafts; [4] chronic rejection does not occur at an early stage. Many doubts have been redressed, but the question whether hand transplantation is justified and worth the enormous effort can nevertheless only be answered on an individual basis. The final judgment can be made only by the patient, and we thus feel it should primarily be the patient’s decision to undergo this type of transplantation! So far, 2 transplanted hands have been lost, one of which was in the first patient who received a hand in the new era of hand transplantation; this, therefore, gave immediate rise to speculations that more hands could be rejected and that hand transplantation should be returned to the research lab [36]. Unfortunately, the circumstances under which these 2 CTAs were lost remain somewhat unclear: the first patient was transplanted in Lyon in 1998 but stopped taking immunosuppressive drugs for an unknown time before progressive acute rejection occurred and he requested amputation [29]. It remains unclear whether rejection might have been reversible. The very first report on this case stated that the
106
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107
48-year-old businessman refused prostheses before transplantation and quit physiotherapy when he left the hospital at day 108 after transplantation to btravel the worldQ instead of continuing physiotherapy under close observation. Assessment of the clinical course in this patient would therefore seem to be difficult and patient selection somewhat questionable [16,29,39,40]. In addition to noncompliance, neuroma formation and degeneration proximal to the amputation level were reported and may have contributed to the unsatisfactory outcome [16]. Precautions must be taken to avoid such experiences in future, and patient consent as well as completion of rehabilitation and regular outpatient controls should be mandatory. Otherwise, such a cost- and labor-intensive procedure is not justified. A psychological investigation protocol was proposed in 2001 and might help better define the suitability of patients requesting a hand transplantation [41]. In the second case, a severe bskin inflammationQ resistant to ballQ treatment resulted in amputation of the hand at 3 years posttransplantation [10]. No details of this patient were published, and the underlying mechanism can only be speculated. It seems unlikely, however, that any unspecific skin inflammation other than rejection or infection would occur after hand transplantation. This case further underlines the importance of detailed investigation and presentation of the data of the limited number of patients who received a CTA. Tolerance induction has been proposed as a prerequisite for hand transplantation, but it is unrealistic that this will be routinely achieved in the near future. Experimental protocols are either not applicable to the clinical situation, not successful in humans, or bear the risk of a graft-vs-host reaction. However, recent developments in immunosuppression, in particular, the introduction of Campath-1H, might reduce the number and/or severity of acute rejections after hand transplantation [1-4]. Recent studies demonstrate a reduction in the number of acute rejections after kidney transplantation and allow for, for example, low-dose calcineurin inhibitor maintenance therapy [2,4]. Such a regimen is expected to reduce side-effects and tumor probability and might result in partial tolerance of the graft. However, how these regimens will influence composite tissue allotransplantation can only be speculated at the moment. On the basis of early experience, we believe that hand transplantation is a valuable therapeutic option for a select group of patients. Acknowledgments This manuscript is based in part on data from the International Registry on Hand and Composite Tissue Transplantation (IRHCTT). The authors thank all participant teams for their data contribution. Participants in the IRHCTT: Erasme University Hospital, Brussels, Belgium (C Van Holder, F Schuind); Hospices Civil de Lyon, Lyon, France (JM Dubernard, P Petruzzo); University of Louis-
ville, Louisville, Ky (WC Breidenbach); Nanfang Hospital, The First Military Medical University, Guangzhou, China (GX Pei); The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (J Zhao); The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjian, China (X Zhang); Innsbruck Medical University, Innsbruck, Austria (R Margreiter, S Schneeberger); Universita di Milano—Bicocca, Monza, Italy (M Lanzetta, S Luccina). References [1] Reyes J, Mazariegos GV, Abu-Elmagd K, et al. Intestinal transplantation under Tacrolimus monotherapy after perioperative lymphoid depletion with rabbit anti–thymocyte globulin (Thymoglobulin). Am J Transplant 2005;5:1430. [2] Shapiro R, Basu A, Tan H, et al. Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with Thymoglobulin or Campath. J Am Coll Surg 2005;200:505. [3] Oike F, Yokoi A, Nishimura E, et al. Complete withdrawal of immunosuppression in living donor liver transplantation. Transplant Proc 2002;34:1521. [4] Watson CJ, Bradley JA, Friend PJ, et al. Alemtuzumab (CAMPATH 1H) Induction therapy in cadaveric kidney transplantation-efficacy and safety at five years. Am J Transplant 2005;5:1347. [5] Starzl TE. Back to the future. Transplantation 2005;79:1009. [6] Irving J. The fourth hand. New York (NY)7 Random House Trade; 2001. [7] Barker JH, Breidenbach WC, Hewitt CW. Second international symposium on composite tissue allotransplantation. Introduction. Microsurgery 2000;20:359. [8] Barker JH, Francois CG, Frank JM, et al. Composite tissue allotransplantation. Transplantation 2002;73:832. [9] Francois CG, Breidenbach WC, Maldonado C, et al. Hand transplantation: comparisons and observations of the first four clinical cases. Microsurgery 2000;20:360. [10] Lanzetta M, Petruzzo P, Margreiter R, et al. The International Registry on Hand and Composite Tissue Transplantation. Transplantation 2005;79:1210. [11] McCabe S, Rodocker G, Julliard K, et al. Using decision analysis to aid in the introduction of upper extremity transplantation. Transplant Proc 1998;30:2783. [12] Lees VC, McCabe SJ. The rationale for hand transplantation. Transplantation 2002;74:749. [13] Jones NF. Concerns about human hand transplantation in the 21st century. J Hand Surg [Am] 2002;27:771. [14] Dickenson D, Widdershoven G. Ethical issues in limb transplants. Bioethics 2001;15:110. [15] Jones JW, Gruber SA, Barker JH, et al. Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team. N Engl J Med 2000;343:468. [16] Dubernard JM, Owen E, Herzberg G, et al. Human hand allograft: report on first 6 months. Lancet 1999;353:1315. [17] Dubernard JM, Petruzzo P, Lanzetta M, et al. Functional results of the first human double-hand transplantation. Ann Surg 2003;238:128. [18] Margreiter R, Brandacher G, Ninkovic M, et al. A double-hand transplant can be worth the effort! Transplantation 2002;74:85. [19] Petruzzo P, Badet L, Lanzetta M, et al. Concerns on clinical application of composite tissue allotransplantation. Acta Chir Belg 2004;104:266. [20] Lanzetta M, Petruzzo P, Vitale G, et al. Human hand transplantation: what have we learned? Transplant Proc 2004;36:664. [21] Germann G. Bilateral hand transplantation—indication and rationale. J Hand Surg [Br] 2001;26:521.
S. Schneeberger et al. / Transplantation Reviews 19 (2005) 100 – 107 [22] Dubernard JM. Composite tissue allografts: a challenge for transplantologists. Am J Transplant 2005;5:1580. [23] Nanobashvili J, Neumayer C, Fugl A, et al. Ischemia/reperfusion injury of skeletal muscle: plasma taurine as a measure of tissue damage. Surgery 2003;133:91. [24] Scheker LR, Hodges A. Brace and rehabilitation after replantation and revascularization. Hand Clin 2001;17:473. [25] Petit F, Minns AB, Dubernard JM, et al. Composite tissue allotransplantation and reconstructive surgery: first clinical applications. Ann Surg 2003;237:19. [26] Kvernmo HD, Gorantla VS, Gonzalez RN, et al. Hand transplantation. A future clinical option? Acta Orthop Scand 2005;76:14. [27] Schneeberger S, Lucchina S, Lanzetta M et al. CMV-related complications in human hand transplantation. Transplantation [in press]. [28] Schneeberger S, Kreczy A, Brandacher G, et al. Steroid- and ATGresistant rejection after double forearm transplantation responds to Campath-1H. Am J Transplant 2004;4:1372. [29] Kanitakis J, Jullien D, Petruzzo P, et al. Clinicopathologic features of graft rejection of the first human hand allograft. Transplantation 2003;76:688. [30] Petruzzo P, Lefrancois N, Kanitakis J, et al. Immunosuppression in composite tissue allografts. Transplant Proc 2001;33:2398. [31] Petruzzo P, Revillard JP, Kanitakis J, et al. First human double hand transplantation: efficacy of a conventional immunosuppressive protocol. Clin Transplant 2003;17:455.
107
[32] Dubernard JM, Burloux G, Giraux P, et al. Three lessons learned from the first double hand transplantation. Bull Acad Natl Med 2002;186:1051 [discussion 1062]. [33] Kanitakis J, Jullien D, Nicolas JF, et al. Sequential histological and immunohistochemical study of the skin of the first human hand allograft. Transplantation 2000;69:1380. [34] Levi DM, Tzakis AG, Kato T, et al. Transplantation of the abdominal wall. Lancet 2003;361:2173. [35] Granger DK, Briedenbach WC, Pidwell DJ, et al. Lack of donor hyporesponsiveness and donor chimerism after clinical transplantation of the hand. Transplantation 2002;74:1624. [36] Kanitakis J, Jullien D, Claudy A, et al. Microchimerism in a human hand allograft. Lancet 1999;354:1820. [37] Giraux P, Sirigu A, Schneider F, et al. Cortical reorganization in motor cortex after graft of both hands. Nat Neurosci 2001;4:691. [38] Neugroschl C, Denolin V, Schuind F, et al. Functional MRI activation of somatosensory and motor cortices in a hand-grafted patient with early clinical sensorimotor recovery. Eur Radiol 2005 [Electronic publication ahead of print]. [39] Hettiaratchy S, Butler PE, Lee WP. Lessons from hand transplantations. Lancet 2001;357:494. [40] Foucher G. Prospects for hand transplantation. Lancet 1999;353:1286. [41] Carta I, Convertino O, Cornaggia CM. Psychological investigation protocol of candidates for hand transplantation. Transplant Proc 2001;33:621.