Bilateral Hand Transplantation: Six Years After the First Case

Authors

  • P. Petruzzo,

    Corresponding author
    1. Department of Surgery, University of Cagliari, Italy
    2. Service de Chirurgie de la Transplantation. Hôpital Edouard Herriot, Lyon, France
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  • L. Badet,

    1. Service de Chirurgie de la Transplantation. Hôpital Edouard Herriot, Lyon, France
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  • A. Gazarian,

    1. Service de Chirurgie de la Transplantation. Hôpital Edouard Herriot, Lyon, France
    2. Chirurgie de la Main et du Membre Supérieur, Polyclinique Orthopédique de Lyon, France
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  • M. Lanzetta,

    1. Service de Chirurgie de la Transplantation. Hôpital Edouard Herriot, Lyon, France
    2. Hand Surgery and Reconstructive Microsurgery San Gerardo Hospital, Monza-University Milan Bicocca, Italy
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  • H. Parmentier,

    1. Service de Chirurgie de la Transplantation. Hôpital Edouard Herriot, Lyon, France
    2. Service d'Orthopédie et de Chirurgie du Membre Supérieur Hôpital Edouard Herriot, Lyon, France
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  • J. Kanitakis,

    1. Service de Chirurgie de la Transplantation. Hôpital Edouard Herriot, Lyon, France
    2. Department of Dermatology/EA 37-32 UCBL, Edouard Herriot Hospital, Lyon, France
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  • A. Sirigu,

    1. Service de Chirurgie de la Transplantation. Hôpital Edouard Herriot, Lyon, France
    2. Institut de Sciences Cognitive, Université Claude Bernard Lyon I, Lyon, France
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  • X. Martin,

    1. Service de Chirurgie de la Transplantation. Hôpital Edouard Herriot, Lyon, France
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  • J. M. Dubernard

    1. Service de Chirurgie de la Transplantation. Hôpital Edouard Herriot, Lyon, France
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* Corresponding author: Palmina Petruzzo, petruzzo@pacs.unica.it , palmina.petruzzo@chu-lyon.fr

Abstract

In this study we present our experience concerning bilateral hand transplantation. Two cases were performed: the first in January 2000 and the second in April 2003. Both recipients received the same immunosuppressive treatment, which was similar to those used in solid organ transplantation, including tacrolimus, prednisone and mycophenolate mofetil while antithymocyte globulins were added for induction. Both recipients presented two episodes of acute rejection (maculopapular lesions) in the first 3 months after transplantation; however, these were easily reversed after a few days increasing oral steroid doses and using topical immunosuppressants. The first recipient presented hyperglycemia and serum sickness while the second recipient suffered a thrombosis of the right ulnar artery and an osteomyelitis of left ulna. All the complications were successfully treated. Functional Magnetic Resonance Imaging (fMRI) showed that cortical hand representation progressively shifted from the lateral to the medial region in the motor cortex. After 6 and 2 years respectively, they showed a relevant sensorimotor recovery particularly of sensibility and activity of intrinsic muscles. They were able to perform the majority of daily activities and to lead a normal social life. The first recipient has been working since 2003. They are both satisfied with their grafted hands.

Introduction

After the first human hand allotransplantation performed in Lyon in September 1998 followed by other cases in USA, China and Italy (1), the technical feasibility of this procedure was clearly demonstrated. Although many members of the scientific and surgical community remained very skeptical about the future of these patients with their grafted hands, we performed the first bilateral hand transplantation in January 2000, followed by another bilateral hand transplantation 3 years later. Indeed, we agree with Ernest Ludwig Kirchner and Viktor Meyer who said that "although not a life-threatening event, the loss of a hand is extremely tragic" (2) and consequently the loss of both hands is even more tragic and may justify a bilateral hand transplantation.

Herein we present our experience concerning bilateral hand transplantation achieved since the first case.

Materials and Methods

Transplantation

The recipient of the first bilateral hand transplantation was a 33-year-old man who suffered a bilateral amputation of hands (3 cm above the wrist) after a blast injury in 1996. He was transplanted on January 13, 2000 (3). The donor was an 18-year-old man, 5 HLA A, B, DR mismatches, negative T- and B-cell cross-match. The immunosuppressive protocol included an initial induction phase with polyclonal antibodies (Thymoglobulin®1.25 mg/kg/day for 10 days), tacrolimus (Prograf® 0.2 mg/kg/day with blood levels between 15 and 20 ng/ml during the first month), prednisolone (Solumedrol® 250 mg on day 1; 1 mg/kg/day for 10 days, then slowly tapered to 20 mg/day), mycophenolate mofetil (Cell Cept® 2 g/day). At 6 years post-transplantation the maintenance treatment consisted of prednisone (Solupred® 5 mg/day), tacrolimus (blood levels between 5 and 10 ng/ml), and mycophenolate mofetil (2 g/day).

The recipient of the second bilateral hand transplantation was a 21-year-old man who underwent amputation of the right forearm and left hand after a crash injury in 2000. He was transplanted on April 30, 2003. The donor was a 48-year-old man, 4 HLA A, B, DR mismatches, negative T- and B-cell cross-match. Immunosuppressive protocol included an induction phase starting at the beginning of the operative procedure with polyclonal antilymphocyte antibodies (Thymoglobulin® 3 mg/kg/day the first day; 2 mg/kg/day the second day and then 1.5 mg/kg/day for a total period of 4 days and an infusion time of 24 h), tacrolimus (0.1 mg/kg/day from day 2 with blood levels between 10 and 15 ng/ml in the first month), prednisolone (250 mg on day 1; 1 mg/kg/day for 10 days, then slowly tapered to 20 mg/day), and mycophenolate mofetil (2 g/day). Maintenance treatment consisted of prednisone (5 mg/day), tacrolimus (blood levels between 5 and 10 ng/ml) and mycophenolate mofetil (2 g/day).

The rehabilitation program started 12 h after surgery; it was intensive (twice a day) and included physiotherapy, electro-stimulation and occupational therapy for the first 12–18 months and continued even after the first patient returned to work.

Evaluation procedures

The patients' general conditions and functional results were evaluated at each anniversary of transplantation. A final and complete evaluation of the first recipient was performed 5 years from transplantation.

The recipients underwent an accurate evaluation in order to detect possible complications correlated to chronic immunosuppressive treatment, such as metabolic complications (hyperglycemia, increase in serum creatinine values or osteoporosis), infectious complications (particularly viral and fungal infections) and neoplasia. In addition, anti-HLA antibodies were monitored by ELISA and microchimerism by PCR analysis of DNA from blood leukocytes. Blood lymphocytes subsets were monitored by FACS. Four-millimeter punch skin biopsies were obtained from the transplanted forearms or hands at various time-points of the follow-up (1, 3, 6, 12 months and then each year) from clinically normal skin or from maculopapular lesions during the rejection episodes. The skin specimens for histology were formalin-fixed and paraffin-embedded. Five-micrometer-thick sections were stained with hematoxylin-eosin or labeled immunohistochemically with antibodies detecting various lymphocyte subsets.

In order to investigate the grafted hands, the patients were submitted to several examinations, such as an angiogram at the first year post-transplantation and then an arterial and venous Doppler every year; radiological evaluation, bone scintigraphy and electromyography at each anniversary.

Specific tests to assess sensitivity and motion recovery were performed in both patients. Protective sensibility, two-point discrimination (2PD) and touch sensation (Semmes-Weinstein test) were investigated. Active range of motion (ROM) of wrist, metacarpophalangeal and interphalangeal joints were registered. Grip and pinch strength were evaluated. Tests, such as Minnesota and Carroll tests, were systematically performed to evaluate functional results.

Functional Magnetic Resonance Imaging (fMRI) was performed before transplantation and at 2, 4, 6, 12 and 18 months after transplantation. We used an event-related fMRI paradigm with regularly spaced events (26 s = 5 scans). During the scans the patients performed flexion/extension movements of the last four digits of both hands, and flexion/extension of the left and right elbow. Before surgery, flexion and extension of the missing fingers were monitored through palpation of the corresponding extrinsic muscle contractions at forearm level.

In addition, at 5 years after transplantation the first patient underwent a final evaluation of the functional results performing Dash score (4), Chen score (5), Ipsen score (6) and the score proposed by the International Registry on Hand and Composite Tissue Transplantation (IRHCTT) (7). In addition, hand movements were measured by 22 sensors embedded in a glove (Cyber glove) and the different postures were then visualized using a software to provide three-dimensional images of the hand.

Results

During the first month post-transplantation the first recipient presented hyperglycemia and serum sickness while the second recipient suffered thrombosis of the right ulnar artery the very first post-operative day. These complications were successfully solved and by the second month post-transplantation the first patient did not present any other complication correlated to the immunosuppressive treatment while the second patient showed osteomyelitis of left ulna, which disappeared after immediate osteosynthesis removal and an antibiotic treatment of 6 months.

The first recipient presented two episodes of acute rejection on days 53 and 82 (8) and the second patient on days 57 and 86. Macroscopically the patients developed asymptomatic skin lesions varying from faint pink macules to erythematous, slightly infiltrated scaly papules. In both cases skin biopsies revealed a perivascular dermal inflammatory infiltrate made of lymphocytes of recipient's origin, expressing mainly the CD3+/CD4+ or the CD3+/CD8+ phenotype, admixed with a low percentage of FoxP3+ Treg cells. These changes corresponded to rejection grades I and II, according to a score recently defined (9). Therefore oral prednisone dose was increased while clobetasol and tacrolimus cream were applied topically. Both episodes resolved clinically and histologically within 10–15 days. Thereafter they did not show other macroscopic or histological signs of acute rejection. Besides these episodes of rejection, the skin presented a normal structure. All cell constituents of the epidermis, dermis and hypodermis were present histologically and/or immunohistochemically at all times, including keratinocytes, Langerhans cells, melanocytes, dermal dendrocytes, mast cells, endothelial cells, Schwann cells, muscle cells, cells of epidermal appendages (sweat glands and pilosebaceous follicles) and adipocytes. Epidermal and adnexal basal keratinocytes showed normal expression of the cell-cycle-associated Ki67 antigen, proving that these structures were capable of self-renewal.

None of the patients developed graft-vs.-host disease or chimerism in peripheral blood. Twelve months since transplantation B- and T-cell populations have resulted normal in both recipients.

Antibodies anti-HLA were never detected.

At present in both cases the grafted hands present normal graft vascularization and bone structure while a slight muscular atrophy is still present.

Sensitivity recovery was shown in both patients with normal pain and cold sensations, without dysesthesia or cold intolerance. In the first recipient, at 6 years after transplantation, Semmes-Weinstein test demonstrated sensitivity recovery on the right hand using 2.83–3.61 monofilaments and on the left hand using monofilaments between 3.22 and 4.08. The 2PD test average test was 6 mm on the right hand (4–9 mm) and 9 mm on the left hand (6–12 mm) with distorted touch perception particularly on the left side. In the second recipient, at 2 years after transplantation, Semmes-Weinstein test demonstrated sensitivity recovery on the right side using 3.22–3.61 monofilaments and on the left side using monofilaments between 3.22 and 3.84. The 2PD test average test was between 7 and 12 mm bilaterally. The active ROM for both patients is shown in Table 1.

Table 1.  Active range of motion (ROM) of forearm, wrist and fingers in the first and second recipient 6 and 2 years after transplantation, respectively
Type of movementFirst recipientSecond recipient
ROM (degrees)
RightLeftRightLeft
Forearm pronation70807080
Forearm supination90909080
Wrist dorsiflexion3001025
Wrist palmarflexion30206560
Wrist ulnar deviation51045
Wrist radial deviation5555
TAM of long fingers180175170210
TAM of thumb503530105

In the first case, motor recovery started with extrinsic muscle function (at present M4+, except for finger extensor which is M3+ on both sides) allowing the patient to grasp large objects as well as to pinch. Intrinsic muscular function began only at a later stage, and at 6 years after transplantation a variable degree of muscle activity was present, particularly at level of thumb opposition (Kapandji's index was 5 on the right-hand side and 3 on the left-hand side), hand lumbrical (1–4 on the right-hand side and 4 on the left-hand side) and interossei (2–4 on the right-hand side and 1–4 on the left-hand side, except for the left-hand, second interosseus was 1). Electromyography confirmed these results showing reduced potentials on the right median nerve, almost normal potentials on ulnar nerve on both sides; a reinnervation was shown bilaterally at thumb level (short abductor) and the abductor of the fifth finger. At 6 years after transplantation a slight improvement at the level of the right median and the left ulnar nerves was reported.

Motor recovery began with extrinsic muscle function also in the second case (2 years after transplantation it was M3+ on the right hand and M4+ on the left hand). Function of intrinsic muscles was observed by 6 months and it was between 3 and 4 on the left and 2 on the right at 2 years after transplantation. It is very interesting to note that the grafted left hand became his dominant hand. The reinnervation process, particularly at the level of median nerves and of the sensitive component of ulnar nerves, was shown also in the second case by electromyography. This process improved significantly during the second year after transplantation.

Muscular power was not strong in both recipients, particularly the first one had an immeasurable grip strength on both sides while the bimanual grip strength was 12 kg; pinch strength was 2.000 kg on the right and 2.250 kg on the left side. In the second patient grip strength was 4 kg on the right side and 8 kg on the left side while pinch strength was between 1 and 2 kg on both sides; in addition he was able to perform a bimanual grip by 6 months. In both cases recognition of small objects was possible using shape, contour and temperature criteria; manual dexterity was tested by specific tests such as the Minnesota and Caroll tests, which showed a normal capacity of reaching, grasping, moving, positioning and turning the objects although in the first recipient there was an impairment to lateral pinch and bimanual grasp. It is remarkable that both patients were able to perform the majority of daily activities by the first year after transplantation (Tables 2 and 3). The first recipient started to work in March 2003. The second patient did not resume work merely because of language difficulties.

Table 2.  Tamai score modified by Ipsen in the first recipient
Right = 76.8 pointsLeft = 67.8 points
  1. Remarks on the score system: Scoring is made on the basis of 100 points.

  2. Final evaluation: excellent = 100–90 points; good = 89–70; fair = 69–40; poor = 39–0.

 Motion
1. Joint movements
 Shoulder% of normal ROM 100Shoulder% of normal ROM 100
 Elbow% of normal ROM 100Elbow% of normal ROM 100
 Wrist% of normal ROM 45Wrist% of normal ROM 43
 % of normal ROM in average 81.6% of normal ROM in average 72.5
 Thumb% of normal ROM 60Thumb% of normal ROM 40
 Fingers (II-IV)% of normal ROM 75Fingers (II-IV)% of normal ROM 63
 % of normal ROM in average 67.5% of normal ROM in average 51.5
Average ROM % of hand joints above the hand
Score = Average ROM % of the extremity × 20/100
 Score =29.82Score =24.8
2. Daily life activities
 Tapping2Tapping2
 Picking up coins2Picking up coins1
 Knotting2Knotting2
 Buttoning2Buttoning1
 Writing1Writing0
 Power grasping2Power grasping2
 Wringing towel2Wringing towel2
 Scissoring1Scissoring1
 Hammering1Hammering1
 Using clothespin1Using clothespin1
Easy = 2; Difficult = 1; Impossible = 0
 Score =17Score =13
 Sensation
 S3S3
Score S0 = 0; S1 = 4; S2 = 8; S3 = 12; S3+= 16; S4 = 20
 Score =16Score =16
 Subjective symptoms
 Pain, cold intolerance, numbness, paraesthesia
Severe =−3; Moderate =−2; Mild =−1
 Score =0Score =0
 Cosmesis
 Atrophy, scar, color change, deformities
Severe =−3; Moderate =−2; Mild =−1
 Score =−1Score =−1
 Patient satisfaction
 Fairly satisfied
Highly satisfied = 20; Fairly satisfied = 15; Satisfied = 10; Poorly satisfied = 5; Not satisfied = 0
 Score =15Score =15
 Job status
 Same = 0; Changed =−5; Cannot work =−10
 Score =0Score =0
Table 3.  The International Registry score system in the first recipient
 Right limbLeft limb
  1. Remarks on the score system: Scoring is made on the basis of 100 points.

  2. Final evaluation: poor = 0–30 points; fair = 31–60 points; good = 61–80 points; excellent = 81–100 points.

Appearance (max 15 points)1414
 Skin texture 
 Hair growth 
 Nail growth 
 Matching with upper limb/body 
Sensibility (max 20 points)1816
 Tactile sensation 
 Protective sensation 
 Discriminative sensation 
 Sweating 
Movement (max 20 points)12.514
 Active ROM 
 Strength 
 Intrinsic muscle activity 
 Cortical reintegration 
Psychological and social acceptance (max 15 points)1414
 Social behavior (max 7 points) 
 Affectiveness (max 5 points) 
 Body image (max 3 points) 
Daily activities and work status (max 15 points)1413
 Driving/riding a bicycle11
 Combing hair/personal hygiene/shaving11
 Pouring water from bottle11
 Grasping glasses11
 Using cutlery/chopsticks00
 Brushing teeth11
 Holding hands11
 Writing10
 Symmetrical use of hands11
 Work status66
Patient satisfaction ad general well-being (max 15 points)1111
 Patient satisfaction 
 Well-being 
 Quality of life 
TOTAL83.582

fMRI showed that before graft, movements of both the right and the left hand activated the most lateral part of the hand area in M1. This region is spatially close to the face area, an observation consistent with reports showing that tactile stimulation of the face induces sensations in the phantom hand of amputees. At 6 months after grafting, the hand representation expanded medially and re-occupied the normal hand region, while overlapping some of the pre-surgery activation. Direct statistical comparison between the pre-surgery and 6-months examinations indicate that lateral M1 sites that were active for hand movements prior to grafting were less active afterward, and that a medial site that was not active before became active after the graft. Interestingly, this medial M1 site corresponds to the anatomical hand knob of the central sulcus, which marks the functional sensorimotor hand representation in normal subjects performing a similar task (Yousry et al., 1997). Elbow movements produced a pattern of motor activations that evolved in time in parallel with the hand motor representation. Pre-operatively, movements of either elbow triggered extensive activation in a contralateral central region of M1, corresponding to the normal location of the hand motor representation. Left elbow movements, in addition, activated a more medial area. At 6 months post-surgery, elbow activations shifted toward an area situated in the upper part of the limb representation and classically defined as the arm region (Penfield & Rasmussen, 1950). Statistical comparison between the first (pre-surgery) and last (6 months) studies demonstrated that different M1 cortical maps were associated with the pre-surgery and post-surgery period: a more central region before the graft, and a more superior medial region 6 months after the graft. Thus, the changes observed in the motor cortex hand and elbow representations were strongly correlated not only in time but also in space. Hand and elbow activations showed a high degree of overlap. The extent of this overlap increased longitudinally from the pre-surgery through the post-surgery studies.

The first bilateral hand transplantation was exhaustively evaluated at 5 years after transplantation. The study performed with the Cyber glove showed the patient's ability to perform a power (on large objects) and a precision grip (on small objects). Moreover, the analysis of the hand posture before contact with the object showed the capacity of the patient to scale the grip size according to object dimensions at the end of the transport phase (10).

Both recipients presented a pre-transplant right dominant hand; however, in the post-transplant period the first patient still has a right dominant hand while in the second patient the left hand became dominant. Using the parameters proposed by Chen the score was II (good); the evaluation performed during the follow-up (3) was based on the score proposed by Tamai and modified by Ipsen, which was the same at 5 years after transplantation (good for the right hand and fair for the left hand; Table 2), and the Dash score was 18. Moreover, the score of the IRHCTT was excellent on both sides as shown in Table 3. These scores were the same at 6 years after transplantation.

The second case was evaluated on the basis of the score proposed by the IRHCTT and it was good on both sides at 2 years after transplantation (Table 4) while Dash score was 18.66.

Table 4.  The International Registry score system in the second recipient
 Right limbLeft limb
  1. Remarks on the score system: Scoring is made on the basis of 100 points.

  2. Final evaluation: poor = 0–30 points; fair = 31–60 points; good = 61–80 points; excellent = 81–100 points.

Appearance (max 15 points)12.512.5
 Skin texture 
 Hair growth 
 Nail growth 
 Matching with upper limb/body 
Sensibility (max 20 points)1818
 Tactile sensation 
 Protective sensation 
 Discriminative sensation 
 Sweating 
Movement (max 20 points)14.515
 Active ROM 
 Strength 
 Intrinsic muscle activity 
 Cortical reintegration 
Psychological and social acceptance (max 15 points)77
 Social behavior (max 7 points) 
 Affectiveness (max 5 points) 
 Body image (max 3 points) 
Daily activities and work status (max 15 points)66
 Driving/riding a bicycle00
 Combing hair/personal hygiene/shaving11
 Pouring water from bottle11
 Grasping glass11
 Using cutlery/chopsticks00
 Brushing teeth11
 Holding hands11
 Writing00
 Symmetrical use of hands11
 Work status00
Patient satisfaction ad general well-being (max 15 points)1111
 Patient satisfaction 
 Well-being 
 Quality of life 
TOTAL6969.5

Discussion

The results achieved in the first bilateral hand transplantation, which were confirmed by the second bilateral hand transplantation, show the feasibility of the surgical procedure, the efficacy of the immunosuppressive protocol, the limited adverse effects and the importance of patient rehabilitation and compliance to ensure functional recovery.

In bilateral hand transplantation we used an immunosuppressive protocol (8) similar to that used in solid organ transplantation and it proved to be sufficient, effective and well tolerated. Some side effects, such as transient hyperglycemia, were evidenced only in the first period after transplantation and they could be avoided by decreasing the doses of the immunosuppressive drugs as it has been done in the second recipient. The second patient presented an infectious complication, which regressed with the appropriate antibiotic therapy. In the majority of cases the toxicity of these drugs is related to the dose and in hand transplantation no over-immunosuppression is necessary. Indeed, in both patients two episodes of acute rejection were reported only in the first 3 months after transplantation and were easily reversed.

Functional recovery is the final goal in upper extremity transplantation. It is a long and complex process, which not only involves preservation of the viability of neural, muscular and sensory end-organ components, but also appropriate and timely reinnervation of neural targets and several degrees of cortical reorganization. The functional outcome expected in limb transplantation is believed to be related to the level of amputation; indeed, our experience shows earlier results in the case of amputation at wrist level. However, late functional outcome appears very encouraging also at forearm level as demonstrated by the results achieved in the second recipient who presented a forearm amputation on the right side.

Complete functional restoration is conditioned by nerve regeneration, which has been demonstrated by immunohistochemical studies of the skin (8), electromyography and sensitive recovery tests. Nerve regeneration was faster than in autoreconstructions as FK506 seems to accelerate axonal regeneration increasing the synthesis of axotomy-induced growth-associated protein (GAP-43) (11) as shown by the appearance of protective sensitivity by 3 months post-transplantation. Furthermore, the fMRI results showed that hand transplantation resulted in global remodeling of the limb cortical map, reversing the functional reorganization induced by the amputation (12). The spatial trajectory of these activations in time further indicates that the cortical rearrangement takes place in an orderly manner: the hand and arm representations tend to return to their original cortical locus. Hence, brain plasticity seems to be accomplished with reference to a pre-amputation body representation. Thus, peripheral input can modify cortical hand organization in sensorimotor regions. It is important to note that subsequent fMRI exams performed at 12 and 18 months after the graft showed no changes in the cortical map. This suggests that once hand neurons have reached their targets brain plasticity processes in the motor areas become stable.

The studies with the Cyber glove in the first grafted patient showed his ability to perform complex movements involving inter-segmental coordination 2 years after transplantation, while he presented normal anticipatory adjustments of hand shape before contact after 3 years. These results show a degree of motor coordination in bilateral hand grafted patients.

Both recipients showed a relevant sensorimotor recovery during the entire period of the follow-up, particularly of sensibility and activity of intrinsic muscles. In our experience, recovery of intrinsic muscles started later and evolved slowly compared to extrinsic muscles. Although both patients presented a limited ROM of their joints, particularly of the wrist, because of fibrosis and adherences with a certain degree of impaired function and a diminished muscular power, they are able to perform the majority of daily activities and live a normal social life, in fact the first patient started to work in March 2003. It is interesting to note that recovery of sensibility and the aesthetic aspect of the grafted hands are very important issues for hand transplantation recipients. For this reason, the IRHCTT adopted its own comprehensive functional evaluation system and score as the favorable social, aesthetic and psychological impact on the patients' well-being must be taken into consideration. These motivations explain the better evaluation of the first case of bilateral hand transplantation obtained with the IRHCTT score compared to that of Chen or Tamai, modified by Ipsen. Although at 6 years after transplantation this patient showed a better self-confidence and a major ability to perform a lot of daily activities, the functional evaluation is the same except for a slight improvement of electromyography results and sensitivity tests, at 5 and 6 years after transplantation.

The rehabilitation program as well as patient compliance seem to condition the functional recovery and for this reason our rehabilitation program started early and was complex. In fact, in the first year it included physiotherapy, electro-stimulation and occupational therapy, then it continued twice weekly over the entire follow-up period. It would be interesting to avoid and decrease the incidence of tenodesis effect, which is the principal cause of joint motion impairment, by starting an earlier active mobilization. Moreover, an appropriate program of rehabilitation should be performed to teach the recipients all the movements to perform daily activities because they seem to have ‘forgotten’ how to carry them out several years after amputation. On the basis of our experience muscular power and ROM should be improved with steady and targeted exercises. The patients need strong motivation, not usually required in solid organ transplant recipients, as the results follow a rigorous protocol of physiotherapy.

In conclusion, on the basis of our experience and that of other teams (1) we believe that 6 years after the first bilateral hand transplantation the achieved results are very encouraging as major adverse effects due to surgery and immunosuppressive regimen did not occur and the patients' quality of life improved considerably. Indeed, patients are satisfied with their grafted hands when they say that ‘the transplantation positively changed their life.’ Definitely, a further follow-up and a larger number of patients with bilateral grafted hands need to be assessed in order to know the future of this composite tissue allograft; however, it certainly started a new era in medicine.

Acknowledgments

We thank Celine Berthillot for her precious collaboration, and Barbara Trudu for proofreading.

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