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Rajiv Midha

Nerve transfer procedures are increasingly performed for repair of severe brachial plexus injury (BPI), in which the proximal spinal nerve roots have been avulsed from the spinal cord. The procedure essentially involves the coaption of a proximal foreign nerve to the distal denervated nerve to reinnervate the latter by the donated axons. Cortical plasticity appears to play an important physiological role in the functional recovery of the reinnervated muscles. The author describes the general principles governing the successful use of nerve transfers. One major goal of this literature review is to provide a comprehensive survey on the numerous intra- and extraplexal nerves that have been used in transfer procedures to repair the brachial plexus. Thus, an emphasis on clinical outcomes is provided throughout. The second major goal is to discuss the role of candidate nerves for transfers in the surgical management of the common severe brachial plexus problems encountered clinically. It is hoped that this review will provide the treating surgeon with an updated list, indications, and expected outcomes involving nerve transfer operations for severe BPIs.

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Sarah Walsh, and Rajiv Midha

In this review the authors intend to demonstrate the need for supplementing conventional repair of the injured nerve with alternative therapies, namely transplantation of stem or progenitor cells. Although peripheral nerves do exhibit the potential to regenerate axons and reinnervate the end organ, outcome following severe nerve injury, even after repair, remains relatively poor. This is likely because of the extensive injury zone that prevents axon outgrowth. Even if outgrowth does occur, a relatively slow growth rate of regeneration results in prolonged denervation of the distal nerve. Whereas denervated Schwann cells (SCs) are key players in the early regenerative success of peripheral nerves, protracted loss of axonal contact renders Schwann cells unreceptive for axonal regeneration. Given that denervated Schwann cells appear to become effete, one logical approach is to support the distal denervated nerve environment by replacing host cells with those derived exogenously. A number of different sources of stem/precursor cells are being explored for their potential application in the scenario of peripheral nerve injury. The most promising candidate, transplant cells are derived from easily accessible sources such as the skin, bone marrow, or adipose tissue, all of which have demonstrated the capacity to differentiate into Schwann cell–like cells. Although recent studies have shown that stem cells can act as promising and beneficial adjuncts to nerve repair, considerable optimization of these therapies will be required for their potential to be realized in a clinical setting. The authors investigate the relevance of the delivery method (both the number and differentiation state of cells) on experimental outcomes, and seek to clarify whether stem cells must survive and differentiate in the injured nerve to convey a therapeutic effect. As our laboratory uses skin-derived precursor cells (SKPCs) in various nerve injury paradigms, we relate our findings on cell fate to other published studies to demonstrate the need to quantify stem cell survival and differentiation for future studies.

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Shelly Lwu and Rajiv Midha

✓A thorough history and physical examination are fundamental to the assessment of patients with brachial and pelvic plexus tumors. Typical of most peripheral nerve tumors, the presenting symptoms and signs are few, and if present, can be subtle. Presenting complaints may include a palpable mass lesion, either symptomatic or asymptomatic; sensory alterations; pain; motor deficits; visceral symptoms; or autonomic dysfunction. Motor deficits are usually a late feature in the pathogenesis of this lesion, and a progressive course of pain and significant sensory and motor deficits suggests a malignant pathological process. A detailed family history may reveal familial syndromes and neurocutaneous disorders that predispose the patient to neoplasia, such as neurofibromatosis. The physical examination should be conducted in a systematic fashion, looking for any cutaneous features and motor and sensory deficits. The mass should also be examined for form, consistency, and mobility. An irregular, firm, and immobile mass suggests a malignant lesion. Complete and accurate clinical information must be gathered to pinpoint the anatomical localization of the lesion and formulate a differential diagnosis.

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Vanessa J. Sammons and Rajiv Midha

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Rajiv Midha, Shudeshna Nag, Catherine A. Munro and Lee C. Ang

Object. Rejection of nerve allografts and loss of regenerated host axons after withdrawal of immunosuppressive therapy poses an ongoing challenge in peripheral nerve repair. The present report is of a blinded prospective controlled study in which an established rat model of nerve allotransplantation is used to examine the effect of fiber type on survival and degeneration of nerve allografts after discontinuation of immunosuppression. The authors hypothesized that sensory axons will selectively resist a rejection response, whereas motor axons will degenerate.

Methods. Four-centimeter nerve segments from ACI rats were grafted into peroneal and sural (mixed) or saphenous (sensory) nerve gaps in Lewis rats. In some rats, L4–6 dorsal root ganglia were ablated before grafting, creating pure motor sural and peroneal nerves. All rats received 12 weeks of immunosuppressive therapy to support nerve regeneration into allografts. Immunosuppression with cyclosporin was then withdrawn. At planned death (12–18 weeks postsurgery), graft tissue was subjected to histomorphometric analysis for evaluation of axon survival and loss.

Graft rejection led to loss of all axons in approximately 60% of the allograft segments. The mixed nerve group was most prone to complete rejection, with significantly lowered axon counts at Weeks 16 and 18 compared with the Week 12 baseline. Axons from the sensory nerve were least likely to degenerate. The pure motor nerve group axons demonstrated intermediate sensitivity, with a selective loss of larger axons at Week 16 and a significant decrease in axon counts from the Week 12 baseline at Week 18.

Conclusions. Whereas the majority of axons are lost after withdrawal of immunosuppressive therapy from nerve allografts, there is a selective survival of axons from cutaneous sensory nerves and smaller-diameter motor fibers. The biological and molecular mechanisms that make some axons impervious to injury remain to be determined.

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Allan H. Friedman, W. Jeffrey Elias and Rajiv Midha

Surgery aimed at repairing damaged peripheral nerves has a long history. Refuting the timehonored nihilism of Hippocrates and Galen that an injured nerve cannot regain function, a few adventurous medieval surgeons attempted to repair severed nerves.6,8 However, the ability of a peripheral nerve repair to restore function was not generally accepted until 1800.1,4 Neurosurgeons, beginning with Harvey Cushing, have had an interest in repairing damaged peripheral nerves.2 Significant progress in the treatment of peripheral nerve injuries resulted from experience with the numerous injuries that occurred during World Wars I and II.3,7,12 Surgeons steadily defined the anatomy of peripheral nerves and developed techniques for decompressing and repairing peripheral nerves.9,11 Kline and Dejonge5 developed an intraoperative electrophysiological technique for detecting axons regenerating across a damaged segment of nerve. In the second 2 decades of the 20th century, distal nerve transfers were rediscovered whereby the proximal end of a less essential nerve is used to reinnervate the distal end of a nerve, providing a more vital function.10

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Antos Shakhbazau, Chandan Mohanty, Ranjan Kumar and Rajiv Midha

Object

Cell therapy is a promising candidate among biological or technological innovations sought to augment microsurgical techniques in peripheral nerve repair. This report describes long-term functional regenerative effects of cell therapy in the rat injury model with a focus on sensory recovery.

Methods

Schwann cells were derived from isogenic nerve or skin precursor cells and injected into the transected and immediately repaired sciatic nerve distal to the injury site. Sensory recovery was assessed at weeks 4, 7, and 10. Axonal regeneration was assessed at Week 11.

Results

By Week 10, thermal sensitivity in cell therapy groups returned to a level indistinguishable from the baseline (p > 0.05). Immunohistochemistry at 11 weeks after injury showed improved regeneration of NF+ and IB4+ axons.

Conclusions:

The results of this study show that cell therapy significantly improves thermal sensation and the number of regenerated sensory neurons at 11 weeks after injury. These findings contribute to the view of skin-derived stem cells as a reliable source of Schwann cells with therapeutic potential for functional recovery in damaged peripheral nerve.