- Email: [email protected]
World Experience After More Than a Decade of Clinical Hand Transplantation: Update on the French Program
World Experience A f t e r M o re Th a n a Decade of Clinical H a n d Tr a n s p l a n t a t i o n : U p d a t e o n t h e Fren c h P ro g r a m Palmina Petruzzo, MD*, Jean Michel Dubernard, MD, PhD KEYWORDS Hand allotransplantation Composite tissue allotransplantation Immunosuppression Acute and chronic rejection Functional recovery
September 23, 1998 and January 13, 2000, respectively. Four bilateral hand transplantations were subsequently performed at the authors’ center. All transplants were funded by a national grant (PHRC) and approved by the Comite´ de Protection des Personnes Participants a` la Recherche Biome´dicale (CCPRB). This article reports on the functional results and complications.
CLINICAL CASES The First Hand Allotransplantation The recipient of the first single hand transplantation, a 48-year-old-man from New Zealand, whose right arm was amputated in an accident in 1984, received the hand from a 41-year-old brain-dead donor on September 23, 1998. Donor and recipient had the same blood type but a complete 6/6 human leukocyte antigen (HLA) mismatch. The T-cell and B-cell crossmatch was negative. The immunosuppressive protocol included induction therapy with antithymocyte globulins and maintenance therapy involving prednisone, 5 mg/d; tacrolimus with blood levels between 5 and 10 ng/mL; and mycophenolate mofetil (MMF), 2 g/d. During the first months the patient presented a well-vascularized hand graft with normal skin
Financial disclosure: The authors have nothing to disclose. Department of Transplantation, Hopital Edouard Herriot, 5, Place d’Arsonval, 69437 Lyon, France * Corresponding author. E-mail address: [email protected] Hand Clin 27 (2011) 411–416 doi:10.1016/j.hcl.2011.07.007 0749-0712/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
hand.theclinics.com
Despite initial controversies and skepticism, hand transplantation has become the most common composite tissue allotransplantation (CTA) performed worldwide. The modern era of clinical CTA was initiated by the first hand transplantation performed in Lyon, France in 1998, despite the fact that several authors did not consider this type of transplant to be justified on an “ideal scientific basis.” At that time only approximately 60 experimental rat and 2 primate limb transplants had shown sustained graft survival.1 However, hand transplantation was rapidly and successfully replicated in the United States, China, Italy, Austria, and Belgium. Currently more than 60 upper extremities have been transplanted.2 Moreover, other CTAs have been performed, such as larynx, face, abdominal wall, and knee. The term CTA means grafting of skin, muscles, nerves, tendons, vessels, and bones as a unit, and provides ideal replacement of missing tissue after traumatic losses, tumor resections, or congenital absences using near-identical parts from a cadaveric donor, enabling reconstruction of “like-with-like.” The goal of CTA, therefore, is not to save lives but rather to restore function and improve quality of life. The first right hand3 and bilateral hand transplantations4 were performed in Lyon, France on
412
Petruzzo & Dubernard and rapid nerve regeneration, which resulted in protective and tactile sensation. He was able to perform most daily activities (eg, grasping a glass, writing) with his grafted right hand. In the first posttransplant month, he developed transient hyperglycemia and a herpes virus infection as side effects of his immunosuppressive treatment. An acute rejection episode occurred 8 weeks posttransplant, which was characterized by erythematous maculopapular lesions disseminated on the skin of the transplanted hand. The lesions regressed after the oral dose of steroids was increased and topical immunosuppressants were used, such as tacrolimus and clobetasol creams. In the first 6 months the patient adhered to his immunosuppressive treatment and physiotherapy protocol. Later, he adhered to the treatment only transiently before ultimately discontinuing it completely. During month 15 posttransplantation, signs of rejection appeared over the skin of the grafted hand and the lesions progressively worsened. The lesions were remarkably similar to those seen in chronic lichenoid cutaneous graft-versushost disease. At the patient’s request the hand graft was amputated in London on March 2, 2001 (29 months after his transplantation). After amputation, various tissue specimens were studied,5 confirming that the more severe pathologic alterations (inflammatory infiltrate and necrosis) were mainly present in the skin component. The other tissues showed milder, if any, alterations. A lymphocytic infiltrate of moderate density forming loose perivascular aggregates was shown in the vicinity of muscles and tendons. Although the results achieved in this first case showed the feasibility of hand allotransplantation, it also showed the great importance of patient compliance to immunosuppressive treatment and
physiotherapy and patient motivation. Remarkably and somehow unexpectedly, the progression of this rejection process seemed slow although the long treatment-free period and the signs were mainly in the skin, and few in deeper tissue.
The Five Cases of Bilateral Hand Allotransplantation Table 1 lists the donor and recipient characteristics of the five patients who underwent bilateral hand allotransplantation. The immunosuppressive protocol in all patients included induction with antithymocyte globulins, and the 1-year maintenance treatment consisted of prednisone (5 mg/d), tacrolimus (blood level between 5 and 10 ng/mL), and MMF (2 g/d). During the follow-up ranging from 1 to 10 years, the transplanted upper extremities looked grossly normal, based on color and texture of the skin, temperature, and hair and nail growth, except in patient 1 who showed nail alteration 5 years after transplantation. Skin biopsies were performed periodically, and histologically the skin showed normal structure and contained all of its normal cell components (Figs. 1 and 2). All patients experienced at least one episode of acute rejection (Table 2), characterized macroscopically by erythematous macules over the graft skin. Acute rejection episodes were characterized mainly by the presence of a dermal perivascular lymphoid infiltrate consisting predominantly of CD31/CD41 T cells occasionally reaching and penetrating the epidermis. These rejection episodes could be reversed through increasing the oral steroid dose in patients 1 and 2; patient 4 experienced only one rejection episode, which was successfully treated with
Table 1 Donor and recipient characteristics Patient 1 Transplantation date Sex Age at transplantation (y) Amputation date Amputation cause Amputation level Donor age (y) HLA mismatches
Patient 3
Patient 4
Patient 5
13.01.2000 30.04.2003 Male Male 33 21
19.02.2007 Female 27
4.07.2008 Male 29
11.07.2009 Male 21
12.01.1996 Explosion R: wrist L: wrist 18 5
28.08.2004 Electrocution R: mid-forearm L: distal forearm 40 4
13.04.2003 Burn R: palm L: wrist 29 3
11.07.2004 Explosion R: distal forearm L: wrist 18 5
Abbreviations: L, left; R, right.
Patient 2
14.09.2000 Crush R: mid-forearm L: distal forearm 45 4
Clinical Hand Transplantation
Fig. 1. Macroscopic aspect (1-A, 2-A, and 3-A) and histology of skin biopsy (1-B, 2-B, and 3-B) in patients 1, 2, and 3, respectively, at the last time point of the follow-up.
intravenous steroids, and in patient 5 the first rejection episode was treated with an intravenous steroid and the second through an increase in the oral steroid dose. In patient 3, the first two episodes were successfully treated with intravenous steroids, the third episode with antithymocyte globulins, and the fourth and fifth episodes with an increase in the oral steroid dose. In addition, after the last episode of rejection in November 2010, a low dose of sirolimus was added to the maintenance therapy for the patient. In all cases, topical immunosuppressants (clobetasol and tacrolimus ointments) were used with any rejection episode. Anti-HLA antibodies were not detected, except in patient 2, who developed transiently anti-HLA class II antibodies in November 2009, which were not detectable 1 year later. None of the patients developed graft-versus-host disease or chimerism in the peripheral blood during follow-up. At the most recent follow-up, histology, MRI, ultrasonography, and high-resolution peripheral quantitative CT scan of all tissue components of the grafted upper extremities detected no alteration that suggested a process of chronic rejection.6
Functional recovery is the final goal in upper extremity transplantation. This process is long and complex, and involves not only 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 that can be expected in limb transplantation is related to the level of amputation; this was confirmed by the authors’ experience showing earlier functional recovery with amputation at the wrist level. However, late functional outcome seems very encouraging also at the forearm level, as shown by the results seen in the second and third recipient in the authors’ series. All of the recipients showed a relevant sensorimotor recovery, which was evaluated using the International Registry on Hand and Composite Tissue Allotransplantation7 (IRHCTT) and the Disabilities of the Arm, Shoulder, and Hand (DASH) scores8 (Table 3). The first two patients were graded as “excellent” based on both scores, whereas a discrepancy was seen in the evaluation of the other patients. The third patient and fifth
413
414
Petruzzo & Dubernard
Fig. 2. Macroscopic aspect (4-A and 5-A) and histology of skin biopsy (4-B and 5-B) in patients 4 and 5, respectively, at the last time point of the follow-up.
patient self-evaluated as “excellent” with the DASH score, although they are “good” and “fair,” respectively, based on the IRHCTT. The fourth patient presented a higher IRHCTT score compared with the
DASH score, having ankylosis of right elbow (as a consequence of his burning accident) and being still unsatisfied of the achieved results, although they are considered encouraging.
Table 2 Acute rejection episodes
Number of episodes POD Banff score
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
2 53, 72 2, 2
3 57, 86, 2759 2, 2, 2
5 16, 271, 635, 951, 1365 2, 2, 3, 2, 3
1 65 2
2 10, 350 2, 2
Abbreviation: POD, post-operative day.
Clinical Hand Transplantation
415
Table 3 Functional recovery of the bilateral hand transplantations expressed by IRHCTT score and DASH score at the last time point of follow-up Patient 1 Follow-up (y) IRHCTT score DASH score
10 R 90.5 4.84
L 86
Patient 2 7 R 85.5 6.25
L 87
Patient 3 3 R 76.5 4.31
L 76
Patient 4 2 R 55.5 31.45
L 61
Patient 5 1 R 56 12.10
L 54
Abbreviations: L, left; R, right.
The IRHCTT is based on objective and subjective parameters, such as skin color and texture; hair and nail growth, which are important markers of hand vascularization and skin trophism; functional results (sensibility tests, measure of active range of motion, pinch and grip strength, intrinsic muscles activity); psychological outcome; social behavior; work status; subjective satisfaction; body image; and well-being. The well-known DASH score is based on patient self-evaluation of disability. All of the recipients showed recovery of protective and tactile sensibility; in addition, a discriminative sensibility (S31, based on Highet scale modified by Dellon and colleagues9) and a partial recovery of intrinsic muscles were shown in the first three patients 2 years after transplantation. Although the short follow-up period of the last two patients does not translate into a discriminative sensibility more than S3 and shows a limited recovery of intrinsic muscles, these patients are already able to perform most daily activities. In the authors’ experience, recovery of intrinsic muscles started later, usually 6 months after transplantation, and evolved slowly compared with extrinsic muscles. However, extrinsic and intrinsic muscle recovery enabled all patients, from 1 to 10 years of follow-up, to perform most daily activities, including eating, driving, grasping objects, stringing a needle, riding a bicycle or a motorbike, shaving, using the telephone, and writing; they live a normal social life, and patients 1 and 5 were able to work again by 3 years and 15 months after transplantation, respectively. Despite the remarkable functional recovery, all patients had a limited range of motion of their joints because of fibrosis and adherences, a variable degree of muscular hypotrophy, and a diminished muscular power. Up to now, none of the recipients showed any decrease in sensorimotor recovery. Cortical reorganization was assessed using functional MRI (fMRI) and transcranial magnetic stimulation. fMRI was performed before and after
transplantation at different time points of the follow-up in the bilateral hand transplant recipients, and the results showed that hand transplantation resulted in global remodeling of the limb cortical map, reversing the functional reorganization induced by the amputation.10 The spatial trajectory of these activations in time further indicates that the cortical rearrangement occurs in an orderly manner: the hand and arm representations tend to return to their original cortical area. Hence, brain plasticity seems to be accomplished with reference to a preamputation body representation. Thus, peripheral input can modify cortical hand organization in sensorimotor regions. Subsequent fMRI examinations performed at 12 and 18 months after transplantation showed no changes in the cortical map, suggesting that once hand neurons have reached their targets, brain plasticity processes in the motor areas become stable. Moreover, transcranial magnetic stimulation11 showed the gradual reappearance of intrinsic hand-muscle representations in the motor cortex, with distinct time courses for right and left muscles and also an asymmetry between the two upper extremities. Although how the level of amputation and the quality of peripheral reconnection interacted with central factors in determining the degree and extent of functional recovery cannot yet be defined, the process of motor cortical plasticity clearly allows the recognition and integration of the transplanted muscles. Risk versus benefit must always be considered carefully, because the main goal of hand transplantation is to improve patient quality of life. The recipients experienced some complications, which were fortunately reversible. Most complications were metabolic and infectious, such as hyperglycemia, which occurred in patients 1 and 5 in the first period after transplantation (first 30 and 10 postoperative days, respectively, and requiring insulin therapy). Currently both patients have normal values of glycemia and hemoglobin A1c. Osteitis of the left ulna was seen in patient 2
416
Petruzzo & Dubernard on day 152, which was successfully treated with antibiotics and removal of metallic materials; oral cellulitis from neutropenia was seen in patient 5 on day 81; and Epstein-Barr virus infection was seen in patient 3 on day 603. Patient 1 developed serum sickness on day 7. Vascular complications also occurred in this series. Thrombosis of the left ulnar artery occurred in patient 2 on day 1, and thrombosis of the right radial artery and left ulnar artery occurred in patient 5 on day 12, which required a bypass between omeral and radial artery on the left side and an embolectomy on the other side. In addition, patient 5 was burned at the back of the left hand and underwent escharectomy with reconstructive surgery. Despite these complications, and the necessity of taking daily immunosuppressive multidrug medication and following a rigorous program of rehabilitation, all of the recipients affirm that the bilateral hand transplantation improved their quality of life. In conclusion, based on the experience and the results achieved in this first trial involving five cases of bilateral hand transplantation, patient compliance and careful recipient selection and evaluation during the follow-up are essential for the success of this type of transplantation.
SUMMARY The Lyon team performed one single and five bilateral hand allotransplantations with a follow-up ranging from 1 to 10 years. The single hand transplantation was the first in the world, and the results showed the feasibility of the surgical technique, the efficacy of the immunosuppressive protocol, the limited adverse effects, and the importance of patient compliance and rehabilitation to ensure graft viability and functional recovery. Based on these findings and the positive results achieved in other single hand transplants performed around the world, the authors performed the first double hand transplantation, followed by four additional cases. All recipients received the same immunosuppressive treatment, including tacrolimus, prednisone, MMF, and antithymocyte globulins for induction. Nevertheless, all patients showed episodes of acute rejection, which could be reversed after additional treatment. In addition, metabolic and infectious complications occurred during the follow-up.
All of the patients who had a bilateral hand transplant showed a relevant sensorimotor recovery, particularly of sensibility and activity of intrinsic muscles. They were able to perform most daily activities and to lead a normal social life. Results seen 12 years after the first hand transplantation are encouraging, because major adverse effects caused by surgery and the immunosuppressive regimen did not occur and the patients’ quality of life improved considerably.
REFERENCES 1. Jones NF. Concerns about human hand transplantation in the 21st Century. J Hand Surg Am 2002;27(5): 771–87. 2. Petruzzo P, Lanzetta M, Dubernard JM, et al. The international registry on hand and composite tissue allotransplantation. Transplantation 2010;90(12):1590–4. 3. Dubernard JM, Owen E, Herzberg G, et al. Human hand allograft: report on first 6 months. Lancet 1999;353:1315–20. 4. Dubernard JM, Petruzzo P, Lanzetta M, et al. Functional results of the first human double-hand transplantation. Ann Surg 2003;238(1):128–36. 5. Kanitakis J, Jullien D, Petruzzo P, et al. Clinicopathologic features of graft rejection of the first human hand allograft. Transplantation 2003;76(4):688–93. 6. Petruzzo P, Kanitakis J, Badet L, et al. Long-term follow-up in composite tissue allotransplantation: in-depth study of five (hand and face) recipients. Am J Transplant 2011;11(4):808–16. 7. Petruzzo P, Lanzetta M, Dubernard JM, et al. The international registry on hand and composite tissue transplantation. Transplantation 2008;86(4):487–92. 8. Gummesson C, Ward M, Atroshi I. The shortened disability of the arm, shoulder and hand questionnaire (Quick DASH): validity and reliability based on responses within the full length DASH. BMC Musculoskelet Disord 2006;7:1–7. 9. Dellon AL, Curtis RM, Edgerton MT. Reeducation of sensation in the hand after nerve injury and repair. Plast Reconstr Surg 1974;53(3):297. 10. Giraux P, Sirigu A, Schneider F, et al. Functional cortical reorganization after transplantation of both hands as revealed by fMRI. Nat Neurosci 2001;4: 691–2. 11. Vargas CD, Aballe´a A, Rodrigues EC, et al. Reemergence of hand-muscle representations in human motor cortex after hand allograft. Proc Natl Acad Sci U S A 2009;106(17):7197–202.
September 23, 1998 and January 13, 2000, respectively. Four bilateral hand transplantations were subsequently performed at the authors’ center. All transplants were funded by a national grant (PHRC) and approved by the Comite´ de Protection des Personnes Participants a` la Recherche Biome´dicale (CCPRB). This article reports on the functional results and complications.
CLINICAL CASES The First Hand Allotransplantation The recipient of the first single hand transplantation, a 48-year-old-man from New Zealand, whose right arm was amputated in an accident in 1984, received the hand from a 41-year-old brain-dead donor on September 23, 1998. Donor and recipient had the same blood type but a complete 6/6 human leukocyte antigen (HLA) mismatch. The T-cell and B-cell crossmatch was negative. The immunosuppressive protocol included induction therapy with antithymocyte globulins and maintenance therapy involving prednisone, 5 mg/d; tacrolimus with blood levels between 5 and 10 ng/mL; and mycophenolate mofetil (MMF), 2 g/d. During the first months the patient presented a well-vascularized hand graft with normal skin
Financial disclosure: The authors have nothing to disclose. Department of Transplantation, Hopital Edouard Herriot, 5, Place d’Arsonval, 69437 Lyon, France * Corresponding author. E-mail address: [email protected] Hand Clin 27 (2011) 411–416 doi:10.1016/j.hcl.2011.07.007 0749-0712/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
hand.theclinics.com
Despite initial controversies and skepticism, hand transplantation has become the most common composite tissue allotransplantation (CTA) performed worldwide. The modern era of clinical CTA was initiated by the first hand transplantation performed in Lyon, France in 1998, despite the fact that several authors did not consider this type of transplant to be justified on an “ideal scientific basis.” At that time only approximately 60 experimental rat and 2 primate limb transplants had shown sustained graft survival.1 However, hand transplantation was rapidly and successfully replicated in the United States, China, Italy, Austria, and Belgium. Currently more than 60 upper extremities have been transplanted.2 Moreover, other CTAs have been performed, such as larynx, face, abdominal wall, and knee. The term CTA means grafting of skin, muscles, nerves, tendons, vessels, and bones as a unit, and provides ideal replacement of missing tissue after traumatic losses, tumor resections, or congenital absences using near-identical parts from a cadaveric donor, enabling reconstruction of “like-with-like.” The goal of CTA, therefore, is not to save lives but rather to restore function and improve quality of life. The first right hand3 and bilateral hand transplantations4 were performed in Lyon, France on
412
Petruzzo & Dubernard and rapid nerve regeneration, which resulted in protective and tactile sensation. He was able to perform most daily activities (eg, grasping a glass, writing) with his grafted right hand. In the first posttransplant month, he developed transient hyperglycemia and a herpes virus infection as side effects of his immunosuppressive treatment. An acute rejection episode occurred 8 weeks posttransplant, which was characterized by erythematous maculopapular lesions disseminated on the skin of the transplanted hand. The lesions regressed after the oral dose of steroids was increased and topical immunosuppressants were used, such as tacrolimus and clobetasol creams. In the first 6 months the patient adhered to his immunosuppressive treatment and physiotherapy protocol. Later, he adhered to the treatment only transiently before ultimately discontinuing it completely. During month 15 posttransplantation, signs of rejection appeared over the skin of the grafted hand and the lesions progressively worsened. The lesions were remarkably similar to those seen in chronic lichenoid cutaneous graft-versushost disease. At the patient’s request the hand graft was amputated in London on March 2, 2001 (29 months after his transplantation). After amputation, various tissue specimens were studied,5 confirming that the more severe pathologic alterations (inflammatory infiltrate and necrosis) were mainly present in the skin component. The other tissues showed milder, if any, alterations. A lymphocytic infiltrate of moderate density forming loose perivascular aggregates was shown in the vicinity of muscles and tendons. Although the results achieved in this first case showed the feasibility of hand allotransplantation, it also showed the great importance of patient compliance to immunosuppressive treatment and
physiotherapy and patient motivation. Remarkably and somehow unexpectedly, the progression of this rejection process seemed slow although the long treatment-free period and the signs were mainly in the skin, and few in deeper tissue.
The Five Cases of Bilateral Hand Allotransplantation Table 1 lists the donor and recipient characteristics of the five patients who underwent bilateral hand allotransplantation. The immunosuppressive protocol in all patients included induction with antithymocyte globulins, and the 1-year maintenance treatment consisted of prednisone (5 mg/d), tacrolimus (blood level between 5 and 10 ng/mL), and MMF (2 g/d). During the follow-up ranging from 1 to 10 years, the transplanted upper extremities looked grossly normal, based on color and texture of the skin, temperature, and hair and nail growth, except in patient 1 who showed nail alteration 5 years after transplantation. Skin biopsies were performed periodically, and histologically the skin showed normal structure and contained all of its normal cell components (Figs. 1 and 2). All patients experienced at least one episode of acute rejection (Table 2), characterized macroscopically by erythematous macules over the graft skin. Acute rejection episodes were characterized mainly by the presence of a dermal perivascular lymphoid infiltrate consisting predominantly of CD31/CD41 T cells occasionally reaching and penetrating the epidermis. These rejection episodes could be reversed through increasing the oral steroid dose in patients 1 and 2; patient 4 experienced only one rejection episode, which was successfully treated with
Table 1 Donor and recipient characteristics Patient 1 Transplantation date Sex Age at transplantation (y) Amputation date Amputation cause Amputation level Donor age (y) HLA mismatches
Patient 3
Patient 4
Patient 5
13.01.2000 30.04.2003 Male Male 33 21
19.02.2007 Female 27
4.07.2008 Male 29
11.07.2009 Male 21
12.01.1996 Explosion R: wrist L: wrist 18 5
28.08.2004 Electrocution R: mid-forearm L: distal forearm 40 4
13.04.2003 Burn R: palm L: wrist 29 3
11.07.2004 Explosion R: distal forearm L: wrist 18 5
Abbreviations: L, left; R, right.
Patient 2
14.09.2000 Crush R: mid-forearm L: distal forearm 45 4
Clinical Hand Transplantation
Fig. 1. Macroscopic aspect (1-A, 2-A, and 3-A) and histology of skin biopsy (1-B, 2-B, and 3-B) in patients 1, 2, and 3, respectively, at the last time point of the follow-up.
intravenous steroids, and in patient 5 the first rejection episode was treated with an intravenous steroid and the second through an increase in the oral steroid dose. In patient 3, the first two episodes were successfully treated with intravenous steroids, the third episode with antithymocyte globulins, and the fourth and fifth episodes with an increase in the oral steroid dose. In addition, after the last episode of rejection in November 2010, a low dose of sirolimus was added to the maintenance therapy for the patient. In all cases, topical immunosuppressants (clobetasol and tacrolimus ointments) were used with any rejection episode. Anti-HLA antibodies were not detected, except in patient 2, who developed transiently anti-HLA class II antibodies in November 2009, which were not detectable 1 year later. None of the patients developed graft-versus-host disease or chimerism in the peripheral blood during follow-up. At the most recent follow-up, histology, MRI, ultrasonography, and high-resolution peripheral quantitative CT scan of all tissue components of the grafted upper extremities detected no alteration that suggested a process of chronic rejection.6
Functional recovery is the final goal in upper extremity transplantation. This process is long and complex, and involves not only 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 that can be expected in limb transplantation is related to the level of amputation; this was confirmed by the authors’ experience showing earlier functional recovery with amputation at the wrist level. However, late functional outcome seems very encouraging also at the forearm level, as shown by the results seen in the second and third recipient in the authors’ series. All of the recipients showed a relevant sensorimotor recovery, which was evaluated using the International Registry on Hand and Composite Tissue Allotransplantation7 (IRHCTT) and the Disabilities of the Arm, Shoulder, and Hand (DASH) scores8 (Table 3). The first two patients were graded as “excellent” based on both scores, whereas a discrepancy was seen in the evaluation of the other patients. The third patient and fifth
413
414
Petruzzo & Dubernard
Fig. 2. Macroscopic aspect (4-A and 5-A) and histology of skin biopsy (4-B and 5-B) in patients 4 and 5, respectively, at the last time point of the follow-up.
patient self-evaluated as “excellent” with the DASH score, although they are “good” and “fair,” respectively, based on the IRHCTT. The fourth patient presented a higher IRHCTT score compared with the
DASH score, having ankylosis of right elbow (as a consequence of his burning accident) and being still unsatisfied of the achieved results, although they are considered encouraging.
Table 2 Acute rejection episodes
Number of episodes POD Banff score
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
2 53, 72 2, 2
3 57, 86, 2759 2, 2, 2
5 16, 271, 635, 951, 1365 2, 2, 3, 2, 3
1 65 2
2 10, 350 2, 2
Abbreviation: POD, post-operative day.
Clinical Hand Transplantation
415
Table 3 Functional recovery of the bilateral hand transplantations expressed by IRHCTT score and DASH score at the last time point of follow-up Patient 1 Follow-up (y) IRHCTT score DASH score
10 R 90.5 4.84
L 86
Patient 2 7 R 85.5 6.25
L 87
Patient 3 3 R 76.5 4.31
L 76
Patient 4 2 R 55.5 31.45
L 61
Patient 5 1 R 56 12.10
L 54
Abbreviations: L, left; R, right.
The IRHCTT is based on objective and subjective parameters, such as skin color and texture; hair and nail growth, which are important markers of hand vascularization and skin trophism; functional results (sensibility tests, measure of active range of motion, pinch and grip strength, intrinsic muscles activity); psychological outcome; social behavior; work status; subjective satisfaction; body image; and well-being. The well-known DASH score is based on patient self-evaluation of disability. All of the recipients showed recovery of protective and tactile sensibility; in addition, a discriminative sensibility (S31, based on Highet scale modified by Dellon and colleagues9) and a partial recovery of intrinsic muscles were shown in the first three patients 2 years after transplantation. Although the short follow-up period of the last two patients does not translate into a discriminative sensibility more than S3 and shows a limited recovery of intrinsic muscles, these patients are already able to perform most daily activities. In the authors’ experience, recovery of intrinsic muscles started later, usually 6 months after transplantation, and evolved slowly compared with extrinsic muscles. However, extrinsic and intrinsic muscle recovery enabled all patients, from 1 to 10 years of follow-up, to perform most daily activities, including eating, driving, grasping objects, stringing a needle, riding a bicycle or a motorbike, shaving, using the telephone, and writing; they live a normal social life, and patients 1 and 5 were able to work again by 3 years and 15 months after transplantation, respectively. Despite the remarkable functional recovery, all patients had a limited range of motion of their joints because of fibrosis and adherences, a variable degree of muscular hypotrophy, and a diminished muscular power. Up to now, none of the recipients showed any decrease in sensorimotor recovery. Cortical reorganization was assessed using functional MRI (fMRI) and transcranial magnetic stimulation. fMRI was performed before and after
transplantation at different time points of the follow-up in the bilateral hand transplant recipients, and the results showed that hand transplantation resulted in global remodeling of the limb cortical map, reversing the functional reorganization induced by the amputation.10 The spatial trajectory of these activations in time further indicates that the cortical rearrangement occurs in an orderly manner: the hand and arm representations tend to return to their original cortical area. Hence, brain plasticity seems to be accomplished with reference to a preamputation body representation. Thus, peripheral input can modify cortical hand organization in sensorimotor regions. Subsequent fMRI examinations performed at 12 and 18 months after transplantation showed no changes in the cortical map, suggesting that once hand neurons have reached their targets, brain plasticity processes in the motor areas become stable. Moreover, transcranial magnetic stimulation11 showed the gradual reappearance of intrinsic hand-muscle representations in the motor cortex, with distinct time courses for right and left muscles and also an asymmetry between the two upper extremities. Although how the level of amputation and the quality of peripheral reconnection interacted with central factors in determining the degree and extent of functional recovery cannot yet be defined, the process of motor cortical plasticity clearly allows the recognition and integration of the transplanted muscles. Risk versus benefit must always be considered carefully, because the main goal of hand transplantation is to improve patient quality of life. The recipients experienced some complications, which were fortunately reversible. Most complications were metabolic and infectious, such as hyperglycemia, which occurred in patients 1 and 5 in the first period after transplantation (first 30 and 10 postoperative days, respectively, and requiring insulin therapy). Currently both patients have normal values of glycemia and hemoglobin A1c. Osteitis of the left ulna was seen in patient 2
416
Petruzzo & Dubernard on day 152, which was successfully treated with antibiotics and removal of metallic materials; oral cellulitis from neutropenia was seen in patient 5 on day 81; and Epstein-Barr virus infection was seen in patient 3 on day 603. Patient 1 developed serum sickness on day 7. Vascular complications also occurred in this series. Thrombosis of the left ulnar artery occurred in patient 2 on day 1, and thrombosis of the right radial artery and left ulnar artery occurred in patient 5 on day 12, which required a bypass between omeral and radial artery on the left side and an embolectomy on the other side. In addition, patient 5 was burned at the back of the left hand and underwent escharectomy with reconstructive surgery. Despite these complications, and the necessity of taking daily immunosuppressive multidrug medication and following a rigorous program of rehabilitation, all of the recipients affirm that the bilateral hand transplantation improved their quality of life. In conclusion, based on the experience and the results achieved in this first trial involving five cases of bilateral hand transplantation, patient compliance and careful recipient selection and evaluation during the follow-up are essential for the success of this type of transplantation.
SUMMARY The Lyon team performed one single and five bilateral hand allotransplantations with a follow-up ranging from 1 to 10 years. The single hand transplantation was the first in the world, and the results showed the feasibility of the surgical technique, the efficacy of the immunosuppressive protocol, the limited adverse effects, and the importance of patient compliance and rehabilitation to ensure graft viability and functional recovery. Based on these findings and the positive results achieved in other single hand transplants performed around the world, the authors performed the first double hand transplantation, followed by four additional cases. All recipients received the same immunosuppressive treatment, including tacrolimus, prednisone, MMF, and antithymocyte globulins for induction. Nevertheless, all patients showed episodes of acute rejection, which could be reversed after additional treatment. In addition, metabolic and infectious complications occurred during the follow-up.
All of the patients who had a bilateral hand transplant showed a relevant sensorimotor recovery, particularly of sensibility and activity of intrinsic muscles. They were able to perform most daily activities and to lead a normal social life. Results seen 12 years after the first hand transplantation are encouraging, because major adverse effects caused by surgery and the immunosuppressive regimen did not occur and the patients’ quality of life improved considerably.
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