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Vascularized Plexus Allotransplantation

A New Hope in Brachial Plexus Palsy?

Farkash, Evan A., MD, PhD1; Leonard, David A., MBChB, PhD2

doi: 10.1097/TP.0000000000002388
Commentaries
Free

1 Department of Pathology, University of Michigan Medical School.

2 Canniesburn Plastic Surgery Unit, and Institute of Molecular, Cell & Systems Biology, University of Glasgow, Glasgow, United Kingdom.

Received 17 July 2018.

Accepted 20 July 2018.

The authors declare no conflicts of interest.

Correspondence: Evan Farkash, MD, PhD, 1150 W. Medical Center Drive, MSRB1 Rm. 7520, Ann Arbor, MI 48109. (efarkash@med.umich.edu).

Brachial plexus injury is associated with significant disability, and can occur throughout life. Shoulder dystocia complicates 1% to 2% of births, of which approximately 20% result in brachial plexus palsy.1 Young adults have a higher incidence of penetrating trauma to the axilla or neck, as well as motorcycle accidents and low-velocity sporting injuries resulting in traction to the upper roots and trunks.2 Compression injuries, due to either malignancy or anatomic variations, such as cervical ribs or congenital fibrous bands, may also be implicated. Later in life, adjuvant radiotherapy to the axilla for treatment of breast carcinoma may also result in brachial plexopathy, manifesting anywhere from 6 months to 20 years after treatment.3

Severe plexus injuries rarely resolve spontaneously and were historically occasionally managed by amputation. The current standard of practice for treatment of severe brachial plexus injuries includes free muscle transfer, multiple nerve transfers, or nerve interposition grafts, with the primary goal of restoring elbow flexion, followed by shoulder stability and motility, and finally hand and wrist function.4 None of these options are without their limitations, however, be it donor site morbidity or simply limited availability of appropriate donor nerves (such as the sural or medial antebrachial cutaneous) for interposition autografts. Furthermore, the challenging biology of nerve regeneration and the proximal level of these injuries have typically been associated with notoriously poor outcomes. There is a need for advanced surgical strategies with the potential for recovery of forearm and finger flexion in particular.

In this issue of Transplantation, Chang et al5 describe a rat model of whole brachial plexus allogeneic interposition transplantation across a full major histocompatibility complex mismatch (RT1n to RT1l). A vascularized neurocutaneous allograft composed of the brachial plexus, subclavian artery and vein, and sentinel skin patch was harvested from Norway rats and implanted into Lewis rats, bridging the C5 to T1 nerve roots with the proximal upper extremity nerves. With this technique, the authors demonstrated recovery of upper extremity function using a grooming test compared with a transected control. Transplantation of the entire plexus showed superior recovery of forearm muscle strength and preservation of muscle mass compared with single and double nerve root transplantation, analogous to the current clinical standard of care.

The transplanted brachial plexus in this study did not merely serve as an inert structural scaffold for axonal regeneration. Without immunosuppression, there was minimal functional recovery on the grooming test and rapid rejection of the sentinel skin patches. Chang et al showed that rats with plexus allografts treated with cyclosporine have similar distal nerve diameters and axon counts compared with rats with plexus autografts. In the absence of cyclosporine, the plexus allografts have extensive axonal swelling and degeneration, and distal nerves have scarring and axonal dropout.

The results are similar to clinical experience with living unrelated and deceased donor nerve allografts used in the repair of brachial plexus injury, in which immunosuppression appears to be important for good outcome.6 However, these have typically been nonvascularized sural grafts, which rely on collateral neovascularization from the nerve bed.7 Vascularized nerve grafts are potentially superior to nonvascularized grafts, due to preservation of Schwann cells and avoidance of central necrosis, particularly in larger diameter grafts. The authors' use of a subclavian pedicle preserves the vascular supply of the entire transplanted plexus.

Although this is a promising preclinical study, there are some hurdles to implementing this approach in humans. Notably, the authors performed brachial plexus transplantation immediately after transection in this study, maximizing the likelihood of nerve regeneration. In humans, brachial plexus repair may be performed weeks or even months after the initial injury, when scarring and atrophy of the nerve roots or motor endplate degeneration following prolonged muscle denervation are likely to limit the maximal recovery. Furthermore, not all patients with brachial plexus injuries will be candidates for transplantation. Patients with proximal avulsion or trauma may lack graftable nerve roots, vascular injury could preclude artery or vein anastomosis, and patients with active or recently treated malignancy would pose a higher risk for immunosuppression.

These hurdles notwithstanding, the field of vascularized composite allotransplantation (VCA) continues to be a growing and active area of study and practice, with recent highly publicized advances in face, hand, and even genital transplantation.8 Recovery of motor and sensory function is a critical component of outcome after VCA. Reennervation resulting in restoration of intrinsic muscle function, and functional 2-point sensory discrimination has been reported after hand transplantation.9 Of note, there is a recent report of total arm transplantation with neurorrhaphy of the recipient plexus to donor nerves resulting in partial recovery of arm function.10 An animal model of vascularized whole brachial plexus transplantation is an important tool for further research into nerve regeneration after VCA, as well as offering potential advances in the management of patients with these challenging and debilitating injuries.

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