Motor recovery began with extrinsic muscle function, allowing all patients to perform grip and pinch activities. Recovery of intrinsic muscles was observed only at a later stage, starting between 9 and 15 months posttransplantation in the majority of patients. This was also confirmed by electromyographic studies in several hands. Extrinsic and intrinsic muscle recovery enabled patients to perform most daily activities, including eating, driving, grasping objects, riding a bicycle or a motorbike, shaving, using the telephone, and writing. When performed, functional magnetic resonance imaging (MRI) demonstrated that after transplantation, the hand representation regained the cortical site that corresponds to the hand knob area in normal subjects.
Patient quality of life improved in more than 75% of the recipients, and going back to work has been a consistent feature for the majority of them. The velocity of sensorymotor recovery was correlated to the level of amputation although the case of bilateral arm transplantation showed a score of 79.5 points (HTSS) on both sides and a DASH score of 37.93 after only 1 year, experiencing a certain difficulty to perform a precision grip.
Complications requiring additional surgical interventions were arterial thrombosis (n=2) and venous thrombosis (n=1) in the first postoperative day, early postoperative necrosis of a small skin area (n=6), and the occurrence of multiple arterio-venous fistulae (n=1). All these events were treated successfully. All the complications correlated to the immunosuppressive treatment are reported in Table 1. One patient presented serum sickness because of antithymocyte globulins treatment. The majority of the recipients experienced opportunistic infections including cytomegalovirus reactivation, with three cases presenting clinical signs of infections, Clostridium difficile enteritis, herpes simplex blisters, herpes zoster, cutaneous mycosis, ulnar osteitis (by Staphylococcus aureus), and bacterial infection of connective tissues of the grafted hands. In addition, 69% of the recipients presented metabolic complications such as transient hyperglycemia (in three cases, it was not reversible and the patients needed hypoglycemic agents), increased serum creatinine values with a single case of end-stage renal disease and consequent hemodialysis 8 years after the hand transplantation, arterial hypertension, Cushing's syndrome, and aseptic necrosis of hip with bilateral replacements. In the follow-up, one patient developed a posttransplant lymphoproliferative disease, and another one developed a basal cell carcinoma of nose.
Since 2002, several reports on the IRHCTT have been already published (6–8). At present, it includes 33 patients corresponding to 49 allografts, 16 bilateral, and 17 single transplantations. The Registry offers the unique opportunity to have a complete view of this new procedure and the possibility to study its evolution. The results showed that hand transplantation is technically feasible with encouraging functional results, and in 2008, the first bilateral arm transplantation was successfully performed. However, it is important an exhaustive pretransplantation study of the recipient to avoid some surgical and infectious complications being hand transplantation the result of a complex reconstructive operation and a long-life immunosuppressive treatment. Thus, the Registry recommends a careful study of stumps (MRI or computed tomography scan, angiography or angio-MRI, muscle, and nerve chart), psychologic evaluation and check up for infections (particularly in case where burn or crush was the cause of amputation), malignancies, renal, or metabolic diseases.
The most common maintenance immunosoppressive regimen used in hand transplantation was low dose of steroid, tacrolimus, and mycophenolate mofetil (MMF); in the follow-up, several teams changed or reduced the treatment to avoid side effects, such as hyperglycemia or increase in serum creatinine values as in solid organ transplantation. In some cases, the teams decided to decrease the immunosoppressive regimen as the recipients did not show any sign of rejection for several years. The switch from tacrolimus to sirolimus was performed to avoid metabolic complications and malignancies.
Although the immunosuppressive drugs currently used in solid organ transplantation were indispensable to ensure graft viability, the majority of patients experienced at least one episode of AR. On the other side, it is important to note that the diagnosis of AR in hand transplantation is easier than in organ transplantation because it is based on visual inspection and skin biopsy, thus explaining the high rate of AR episodes reported in this field of transplantation. Therefore, a constant watch over the grafts and periodic biopsies are recommended. The choice of AR treatment is based on the Banff score grade, the frequency of the episodes, and the sensibility to steroid treatment. In the majority of cases, the episodes were reversed increasing oral steroid dose or using intravenous steroids plus local immunosuppressants. The early diagnosis and the prompt treatment of the AR episodes are indispensable to avoid graft loss.
Currently, no case of chronic rejection has been reported to the Registry; however, one patient presented acute ischemia of the transplanted hand, which was removed and showed intimal hyperplasia of the vessels. Myointimal proliferation of vessels is one of the classic features of chronic rejection; consequently, it might be considered as the first case of chronic rejection.
The majority of the reported side effects were infections and metabolic complications. Most of them were transient and reversible, and perhaps, some of them might be avoided using lower doses of immunosuppressive drugs or changing them and performing a long-term prophylaxis for Candida, Pneumocystis carinii, and cytomegalovirus (9). One patient required hemodialysis as he developed end-stage renal disease also because of calcineurin inhibitors (indeed increases in creatinine values are often correlated to the high doses of tacrolimus). For this reason, four patients were switched to sirolimus, and other two patients received low dose of tacrolimus and everolimus. Hyperglycemia is a common side effect reported by several teams in the first period after the transplantation, and it is probably because of the high doses of steroid and tacrolimus. Other two recipients developed a malignancy, which was treated successfully. Hand allotransplantation as other CTAs is limited by the current need for long-life multidrug immunosuppression to prevent rejection. Several experimental studies tried to induce tolerance administrating bone marrow in the form of vascularized bone graft with demonstration of bidirectional trafficking of bone marrow cells between donor and recipient. The question how this strategy can be translated into a clinical trial remains to be addressed; indeed, the administration of donor bone marrow cells in some cases of CTAs did not induce tolerance (10). At present, further researches are needed to develop donor-specific tolerance.
The balance risk/benefit must always be considered because the goal of hand transplantation is to improve patient quality of life. For this reason, the evaluation of functional outcome was important, and the Registry decided to adopt its own functional score system. It is important to note that in addition to the HTSS (2), the DASH (3) score has been also used to compare the results obtained with the two different systems of evaluation and grading. The Registry score allows an evaluation of both cosmetic and functional results, and it takes into account “what really happened to the patient” after hand transplantation. It includes assessing his or her psychologic outcome, social behavior, work status, subjective satisfaction, body image, and well being. It measures the “ability and performances” of the grafted patients instead of measuring the disabilities of proximal or distal parts of upper extremities. One important aspect assessed by the HTSS is the appearance of the grafted hands as skin color and texture, hair, and nail growth are important markers of hand vascularization and skin trophism and of chronic rejection. The importance of body image must specifically be taken into consideration, as the patient has been carrying and, therefore, showing his or her own disability for some time, causing a severe adjustment of his or her personality and ability to engage in social and affective relations.
From a functional point of view, a remarkably good recovery of sensibility has been documented in all transplanted hands, while recovery of motor function has enabled the patients to perform most daily activities. It is interesting to note that bilateral hand transplanted patients were only slightly more satisfied than unilateral hand grafted patients and that motor and sensory functions improved at least the first 5 years after transplantation in unilateral and bilateral hand transplantations. Functional recovery has been well documented, and it is based on not only nerve regeneration and cortical reorganization (11) but also good compliance of the recipient to the long and hard rehabilitation program. In conclusion, patient compliance to the immunosoppressive regimen and to the rehabilitation program and his or her careful evaluation before and after transplantation are essential in hand transplantation.
This study presents some limitations that are principally because some teams did not report their cases to the Registry, such as those from China, Germany, and Pittsburgh, and other teams did not fill all the items of the Registry. Moreover, the rejection grading scales were adjusted on the basis of the Banff CTA classification, which was adopted in 2007.
MATERIALS AND METHODS
The total number of transplants reported to IRHCTT was 49 upper extremity transplantations, 16 bilateral, and 17 single transplantations for a total of 33 patients and a follow-up period ranging from 1 to 142 months (median 48 months).
Because it has been impossible to obtain complete information on patients grafted in China, they are not included in this analysis. However, Chinese patient and graft survival are here reported as GX Pei and DY Xiang kindly informed the Registry about them.
In China, from September 1999 to March 2009, 15 hand/forearm/palm/digit allotransplantations (5 unilateral and 1 bilateral hand transplantations, 3 unilateral and 2 bilateral forearm transplantations, 1 palm transplantation, and 1 thumb transplantation) have been performed in 12 patients (11 males and 1 female). Follow-up period ranged from 12 to 116 months.
Recipient and donor characteristics are reported in Tables 2 and 3. Crossmatch was always negative, whereas there were two cases of unmatched gender. Upper extremities were harvested in heart-beating donors in 26 cases. In 19 donors, limbs were harvested before solid organs, whereas in the remaining cases, limbs were procured after solid organs. University of Wisconsin solution was used for cold flush and limb preservation in 27 cases, heparinized saline solution in 2 cases, IGL-1 solution in 3 cases, and histidine-tryptophan-ketoglurate solution in 1 case. Cold ischemia time ranged from 30 min to 12 hr (mean time 6 hr), largely depending on local circumstances including geographical distance between donor and recipient hospital.
The repair sequence of the different tissues varied considerably; however, in 100% of hands, bone fixation was first performed, followed by arterial and venous anastomoses in 51% of cases, then suture of nerves and tendons. Two arteries were always anastomosed and a variable number of veins (two veins in 44.6% of limbs). Median and ulnar nerves were always repaired, whereas the radial nerve was reconstructed in only 45% of hands. In 52.5% of cases, tendon repair was achieved by suturing individual tendons, whereas in the remaining cases, it was necessary to repair them suturing a single flexor or extensor recipient tendon to a few donor tendons to achieve a group suture as described by Pulvertaft.
All patients followed an intense rehabilitation program (five times a week for a period lasting 365 days in the majority of cases), which included physiotherapy, electrostimulation, and occupational therapy. The induction therapy included antithymocyte globulins (n=16) or alemtuzumab (n=8) or basiliximab (n=5), associated to tacrolimus, MMF, and steroids. Only two patients did not receive any induction, and they were treated with tacrolimus, MMF, and steroids plus a steroid ointment.
A triple drug combination was used for maintenance therapy based on tacrolimus, MMF, and steroids; in the first 3 months after transplantation, all recipients received tacrolimus, 27 of them received steroids, and 26 received MMF. During the follow-up period, eight recipients were switched from tacrolimus to sirolimus; in five cases, steroids were withdrawn; two recipients received steroids and low dose of tacrolimus and everolimus; and two received sirolimus and MMF.
Topical applications of steroid and tacrolimus ointments were performed in the recipients who did not receive induction therapy, in two of the patients who did not receive the triple immunosuppressive regimen, and in the majority of cases of AR. In the postoperative period, wide-spectrum antibiotics were given in 100% of the cases. A complete prophylaxis covering Candida, cytomegalovirus, and Pneumocistis jirovecii potential infections was given in 40% of the cases. A limited prophylaxis was used in 30% of the cases, and no prophylaxis was administered in 30% of the cases.
The functional results were evaluated on the basis of the HTSS (2), which evaluates six aspects with different weight for a total of 100 points: appearance (15 points), sensibility (20 points), motility (20 points), psychologic and social acceptance (15 points), daily activities and work status (15 points), and patient satisfaction and general well being (15 points). A total result of 81 to 100 points is graded as an excellent outcome, 61 to 80 as good, 31 to 60 as fair, and 0 to 30 as poor. The DASH score (3) of the population from the United States is 10.10, and higher values indicate disability. During the follow-up, the annual form, the HTSS, and the DASH score have to be filled for all hand-grafted patients.
The authors thank Prof. Barbara Trudu for proofreading.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
Composite tissue allotransplantation; Hand allotransplantation