Effect of perineurial window size on nerve regeneration, blood-nerve barrier integrity, and functional recovery

End-to-side neurorrhaphy is used clinically to reconstruct nerve injuries when the lack of a suitable proximal nerve stump precludes conventional approaches to microsurgical repair. In end-to-side neurorrhaphy, the distal stump of a transected nerve is sutured to the side of an intact nerve that serves as an axon donor. Prior studies suggest that this perineurial window is a prerequisite for effective nerve regeneration into the recipient nerve. However, the optimal size for this perineurial window remains uncertain. This study evaluated the effect of perineurial window size on collateral axonal sprouting, blood-nerve barrier architecture, and functional impairment of the donor nerve. One hundred twenty Lewis rats were randomized to 1 and 5 mm perineurial window groups and examined at serial time points. The 5 mm perineurial window group exhibited significantly greater fiber counts at the repair zone than the 1mm group within 4 weeks (p < 0.005). Marked breakdown of the blood-nerve barrier was present 2 week postoperatively and resolved by 4 weeks regardless of 1 versus 5 mm perineurial window size. Tibial function indices in both groups normalized between 4 and 6 weeks postoperatively. A large (5 mm) perineurial window induced greater collateral sprouting or regenerative response than a small (1 mm) perineurial window without increasing cross sectional nerve injury or delaying functional recovery.     

Treatment of a proximal accessory nerve injury with nerve transfer

OBJECTIVE AND HYPOTHESIS: This study presents a case report of a patient who sustained an iatrogenic proximal accessory nerve injury that was treated with a medial pectoral to accessory nerve transfer. STUDY DESIGN: Case study. MATERIALS AND METHODS: Chart of one patient who was treated with a medial pectoral to accessory nerve transfer was reviewed. RESULTS: Five months after excision of a branchial cyst that resulted in a very proximal injury to the accessory nerve, this patient underwent a medial pectoral to accessory nerve transfer. At final follow-up, 3 years after surgery, the patient had full abduction overhead with some residual shoulder/scapular discomfort and mild scapular winging. CONCLUSION: The medial pectoral to accessory nerve transfer provides a viable surgical option with good reinnervation of the trapezius muscle in patients with a proximal accessory nerve injury where standard nerve repair or graft techniques are not feasible.     

Baiting the cross-face nerve graft with temporary hypoglossal hookup

BACKGROUND: Cross-face nerve grafting yields inconsistent neural regeneration, and methods that promote more robust axonal traversing of the graft would expand the indications for this procedure. OBJECTIVE: To test the hypothesis that hooking a cross-face nerve graft distally to a source of denervated muscle, rather than leaving it in the subcutaneous space, would positively affect neural ingrowth across the graft, based on elaboration of neurotrophins from the musculature. METHODS: Twenty-four rats underwent cross-face nerve grafting in which the right facial nerve buccal branch was transected and coapted to the graft. The graft was placed across the neck and into the left side of the face. The distal end of the graft was placed either in the left subcutaneous space, coapted to the marginal mandibular branch of the left facial nerve, or coapted to the distal stump of the transected left hypoglossal nerve. Eight control animals underwent right buccal branch transection and placement of a cross-face nerve graft without any proximal and distal hookup. After 12 weeks, all experimental groups underwent hookup of the distal nerve graft to the left facial nerve buccal branch. Vibrissal function was assessed during the ensuing 12 weeks, and then the graft was harvested for histomorphometric analysis. RESULTS: After 12 weeks, there was a significant difference in axon counts between the group coapted distally to the tongue (hypoglossal hookup) and that coapted to the facial musculature (marginal hookup). Twelve weeks later, after distal cross-face nerve graft hookup, this difference was not statistically significant, although the hypoglossally baited group demonstrated statistically significantly greater fiber maturity. Recovery of vibrissal movement did not differ among treatment groups. CONCLUSION: Baiting the cross-face nerve graft via temporary hookup to the distal hypoglossal nerve and tongue musculature appears to improve nerve ingrowth through a nerve graft across the face, although a corresponding improvement in facial muscle function was not observed.     

Anti-CD40 ligand monoclonal antibody induces a permissive state, but not tolerance, for murine peripheral nerve allografts

Anti-CD40 ligand monoclonal antibody prevents the interaction between CD40 and its T-cell-based ligand, thereby resulting in selective inhibition of T cell costimulation without pan-T-cell suppression. This antibody has found application in several animal models of solid organ transplantation. This study investigated use of anti-CD40 ligand antibody to promote acceptance of nerve allografts. In Experiment 1, 40 BALB/cj mice with tibial nerve transplants were administered anti-CD40 ligand antibody, a control antibody, or no treatment. In Experiment 2, 40 BALB/cj mice underwent the same regimen as in Experiment 1, but were later challenged with a second nerve allograft 3 weeks after discontinuation of treatment. Animals treated with anti-CD40 ligand antibody in Experiment 1 exhibited improved functional recovery and greater mean fiber count, fiber density, and percent nerve fiber than animals treated with control antibody or no antibody (P < 0.05). These permissive effects on nerve regeneration were associated with immune unresponsiveness on Elispot assay. The benefit of anti-CD40 ligand therapy did not persist after withdrawal of treatment (Experiment 2). Active blockade of the CD40 costimulatory pathway with murine anti-CD40 ligand antibody therefore induces a permissive state conducive to nerve regeneration across allografts but does not establish long-term tolerance.     

End-to-side neurorrhaphy and lateral axonal sprouting in a long graft rat model

OBJECTIVE/HYPOTHESIS: Controversy exists regarding collateral axonal sprouting across an end-to-side neurorrhaphy to provide functional motor reinnervation of a target organ without compromise of the donor nerve. Rat models may be limited in the study of end-to-side repair given potential contamination from the proximal nerve stump of the recipient distal nerve and the use of antagonistic muscle groups for donor and recipient. The current study attempts to address these issues by using a rat model in which an end-to-side coaptation is performed with a long graft interposed between the intact donor tibial nerve and the divided, distal contralateral tibial nerve. MATERIALS AND METHODS: The graft used in proximal end-to-side coaptation consisted of both sciatic nerves in a donor syngeneic animal. The distal repair to the contralateral tibial nerve was done immediately or in a delayed fashion to allow potential motor axons to transverse the graft before division of the recipient tibial nerve. RESULTS: After 24 weeks, axons were noted to transverse the entire distance of the graft and into the contralateral distal posterior tibial nerve. A significant increase in axonal numbers was observed in the immediate repairs compared with the delayed. No animal recovered functional motor ability on the contralateral side as assessed by walking tracks. CONCLUSIONS: These findings suggest the importance of immediate distal neurotrophic factors in encouraging nerve regeneration even in a long graft end-to-side repair. Our model is successful in demonstrating innervation through an end-to-side coaptation but questions its use given the lack of motor recovery.     

Brachial plexus injuries

Severe trauma to the brachial plexus most often occurs in young adult men and is a crippling injury that requires management in a timely fashion for optimal functional recovery and pain control. The surgical management of such injuries is well established, and the techniques continue to evolve. Current management options consist of primary repair in the acute setting, neurolysis, neuroma resection and nerve grafting, motor and sensory nerve transfers, and muscle and tendon transfers. Shoulder andwrist fusion can also play a role in the overall management of these patients. The best operative plan varies depending on the patient's level and extent of injury and the surgeon's preference and experience. The pre- and postoperative care of these patients is ideally managed by a team that has experience with such problems, including personnel knowledgeable in their postoperative rehabilitation. The total reconstructive process generally consists of more than one operation, and the postoperative rehabilitation is long and intensive. Nevertheless, with a highly motivated patient and a dedicated and specialized surgical team, the prognosis for functional recovery is good, and these patients can still lead productive and satisfying lives.     

Pathophysiology of nerve injury

The response to nerve injury is a complex and often poorly understood mechanism. An in-depth and current command of the relevant neuroanatomy, classifications systems, and responses to injury and regeneration are critical to current clinical success. Continued progress must be made in our current understanding of these varied physiologic mechanisms of neuro-regeneration if any significant progress in clinical treatments or outcome is to be expected in the future. Reconstructive surgeons have in many ways maximized the technical aspects of peripheral nerve repair. However, advances in functional recovery may be seen with improvements in sensory and motor rehabilitation after peripheral nerve surgery and with a combined understanding of the neurobiology and neurophysiology of nerve injury and regeneration.     

Effects of delaying FK506 administration on neuroregeneration in a rodent model

FK506 is an immunosuppressant drug that has been shown experimentally to stimulate nerve growth and speed functional recovery, when administered immediately after peripheral nerve injury. However, the clinical scenario of a peripheral nerve injury is often associated with either a delayed diagnosis or reconstruction. The purpose of this study was to determine the efficacy of FK506 on neuroregeneration with delayed administration. Thirty-two Lewis rats underwent tibial nerve transection with immediate repair. Animals were left untreated, or were treated with daily injections of FK506 (2 mg/kg), started on the day of surgery, postoperative day 3, or postoperative day 5. Animals underwent walking track analysis to assess functional nerve recovery. Nerves were harvested for histomorphometric analysis on postoperative days 21, 28, and 42. Histomorphometry demonstrated that all treatment groups, regardless of the time of drug initiation, demonstrated evidence of enhanced neuroregeneration, compared to the untreated group. Histomorphometric data from groups harvested on day 21 demonstrated a statistically significant improvement in neuroregeneration in the immediate and 3-day delay groups. Therefore, the beneficial effects of FK506 on neuroregeneration are not restricted to immediate administration, but these effects significantly diminish when FK506 is administered 3 days after nerve injury.