Gwendolyn M. Hoben

Nerve Transfers to Restore Upper Extremity Function in Cervical Spinal Cord Injury: Update and Preliminary Outcomes.

Background: Cervical spinal cord injury can result in profound loss of upper extremity function. Recent interest in the use of nerve transfers to restore volitional control is an exciting development in the care of these complex patients. In this article, the authors review preliminary results of nerve transfers in spinal cord injury. Methods: Review of the literature and the authors’ cases series of 13 operations in nine spinal cord injury nerve transfer recipients was performed. Representative cases were reviewed to explore critical concepts and preliminary outcomes. Results: The nerve transfers used expendable donors (e.g., teres minor, deltoid, supinator, and brachialis) innervated above the level of the spinal cord injury to restore volitional control of missing function such as elbow extension, wrist extension, and/or hand function (posterior interosseous nerve or anterior interosseous nerve/finger flexors reinnervated). Results from the literature and the authors’ patients (after a mean postsurgical follow-up of 12 months) indicate gains in function as assessed by both manual muscle testing and patients’ self-reported outcomes measures. Conclusions: Nerve transfers can provide an alternative and consistent means of reestablishing volitional control of upper extremity function in people with cervical level spinal cord injury. Early outcomes provide evidence of substantial improvements in self-reported function despite relatively subtle objective gains in isolated muscle strength. Further work to investigate the optimal timing and combination of nerve transfer operations, the combination of these with traditional treatments (tendon transfer and functional electrical stimulation), and measurement of outcomes is imperative for determining the precise role of these operations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Vascularization is delayed in long nerve constructs compared with nerve grafts.

Introduction: Nerve regeneration across nerve constructs, such as acellular nerve allografts (ANAs), is inferior to nerve auto/isografts especially in the case of long defect lengths. Vascularization may contribute to poor regeneration. The time course of vascular perfusion within long grafts and constructs was tracked to determine vascularization. Methods: Male Lewis rat sciatic nerves were transected and repaired with 6 cm isografts or ANAs. At variable days following grafting, animals were perfused with Evans Blue albumin, and grafts were evaluated for vascular perfusion by a blinded observer. Results: Vascularization at mid‐graft was re‐established within 3–4 days in 6 cm isografts, while it was established after 10 days in 6 cm ANAs. Conclusions: Vascular perfusion is reestablished over a shorter time course in long isografts when compared with long ANAs. The differences in vascularization of long ANAs compared with auto/isografts suggest regenerative outcomes across ANAs could be affected by vascularization rates. Muscle Nerve 54: 319–321, 2016

The Use of Nerve Transfers to Restore Upper Extremity Function in Cervical Spinal Cord Injury

Nerve transfer surgery to restore upper extremity function in cervical spinal cord injury (SCI) is novel and may transform treatment. Determining candidacy even years post‐SCI is ill defined and deserves investigation.

Abstract 53: Discrepancies in Senescence and Protein Expression from Cells in Nerve Autografts Compared to Injured Nerve

RESULTS: Axon counts clearly demonstrated disproportionately reduced regeneration in the longer graft compared to the short graft when measuring at equivalent distances to the spinal cord: the number of regenerated axons in the long graft was 57% of those regenerated in the short graft. Additionally, retrograde labeling showed significantly fewer motoneurons were found to be regenerating axons to long grafts compared to the short graft repairs. Cell composition amongst the different grafts and injured nerve were surprisingly consistent: groups had similar total numbers of cells and similar proportions of fibroblasts, Schwann cells, and macrophages. Immunohistochemical analysis showed an increased percentage of cells with senescent markers in the long grafts and in the “normal” nerve proximal to the graft. While gene expression for senescent markers was increased in both long and short nerve grafts, these markers remained elevated over time in the long grafts. Interestingly, GDNF and IL-6 expression was elevated in the long grafts compared to the short. Finally, immunohistochemistry revealed increased NOTCH signalling in the long grafts. CONCLUSION: Comparison of short and long grafts, at points equidistant to the spinal cord, showed reduced axon regeneration and reduced number of motoneurons regenerating axons. Given this reduced regeneration in the presence of a long graft and the finding that cellular composition was unchanged, immunohistochemistry and gene expression were used to identify gene and protein expression differences in the grafts.The longer grafts were found to have a greater proportion of senescent cells and the nerve proximal to the graft even showed senescent changes. Gene expression associated with senescent was increased in the grafts but retained over time in the longer grafts. Prior work has linked increased NOTCH signalling to reduced neurite extension from dorsal root ganglia neurons and the current work links increasing graft length with increased NOTCH signalling. These protein and gene expression changes give insight as to the poor clinical outcomes associated with autografts and provide targets for improvement.

Abstract 63: senescent schwann cells inhibit nerve regeneration in a short conduit model.

PurPose: Nerve injuries requiring long distances for axonal regeneration are associated with poor functional outcomes. Our laboratory has shown that increased nerve graft length (both isografts and acellular nerve allografts) results in decreased regeneration and accumulation of senescent SCs (SenSCs) both in the graft and in the nerve distal to the graft. Senescent cells activate the senescent associated secretory phenotype (SASP), which is rich in inflammatory proteins, ECM remodeling proteins, and other factors. We hypothesize that SenSCs impede axonal regeneration after injury. To test this hypothesis, we examined whether SenSCs directly limit nerve regeneration by transplanting cultured SCs induced to a senescent state into a nerve gap injury model. We measured changes to gene expression associated with nerve regeneration in these SenSCs to explore a mechanism for the limited regeneration.