Tibial Nerve Repair in a Dog Model: Effect of Local and Systemic Administration of Erythropoietin.

PURPOSE: This study aimed to assess the effectiveness of erythropoietin (EPO) as a novel treatment for peripheral nerve injury after surgical repair of an induced tibial nerve injury in dogs. METHODS: Mongrel dogs (n = 27) were randomly divided into three equal groups. A complete tibial nerve injury was induced and repaired directly by stay sutures and the local application of 1 mL fibrin glue (control group). In the "systemic" group, 20,000 IU of EPO were given subcutaneously immediately after surgery and on the first and second days after surgery. In the "local" group, EPO was mixed with fibrin glue at 1,000 IU/mL. Lameness score, compound muscle action potential of the tibial nerve, and serum biochemical and histopathological examinations were performed to evaluate the treated dogs over the study period (12 weeks). RESULTS: EPO significantly improved the lameness score and compound muscle action potential in both the systemic and local groups. After 12 weeks, systemic and local groups showed earlier improvement in lameness, reaching scores of -1 and 0, respectively, in comparison with the control group, which did not reach a score of -1. The histological study revealed a normal architecture of the nerve bundles within connective tissue. The axons were aligned in a regular pattern, whereas the control group had disrupted and degenerated nerve axons with large gaps in between. CONCLUSIONS: EPO has an accelerating healing effect after tibial nerve surgical repair. Local EPO mimics systemic EPO treatment without systemic adverse effects. These findings indicated that EPO has a potential role in tibial nerve recovery and nerve regeneration. CLINICAL RELEVANCE: The findings of the present experimental study supported the beneficial effects of systemic and local EPO when combined with peripheral nerve surgical repair, potentially improving functional outcomes and enhancing faster recovery.

Late Results of Early End-to-End Repair in Sciatic Nerve Injuries.

OBJECTIVE: Mechanisms of sciatic nerve injury include gunshot injury, sharps injury, injection injury, contusion, femoral fracture injury, and iatrogenic injury due to fracture surgery. Regardless of the type of injury, patients undergoing sciatic nerve repair have poor motor and sensory outcomes. In this study, we compared the late outcomes of a group of patients in whom the author performed an early end-to-end anastomosis for sciatic nerve sharps injury and another group of patients with a similar injury who were not operated on but left to natural history. METHODS: The sciatic nerve, comprising two primary divisions with distinct muscle innervations, was subject to separate examinations. Group 1 (n=10, study group) underwent tibial division anastomosis, while Group 2 (n=12, control group) received no surgical intervention involving the tibial division. Similarly, Group 3 (n=11, study group) underwent peroneal division anastomosis, while Group 4 (n=14, control group) encompassed subgroups that did not undergo peroneal division surgery. RESULTS: In Group 1, the rate of gain in plantar flexion muscle strength was significantly higher (p < 0.05) compared to Group 2. Furthermore, the sensory examination gain level ratio within the tibial domain was significantly greater (p < 0.05) in Group 1 than in Group 2. Additionally, Group 1 exhibited a significantly higher rate (p < 0.05) of detection of regeneration and reinnervation findings in electromyography (EMG) compared to Group 2. CONCLUSION: When evaluating the long-term outcomes following early end-to-end anastomoses of the sciatic nerve, it becomes evident that while significant improvements are observed when compared to individuals without anastomosis, the positive impact of surgical interventions on motor and sensory gains in daily life remains limited. Nevertheless, we contend that early surgical intervention holds potential advantages in terms of patient management.

Electroacupuncture Induces Bilateral S1 and ACC Epigenetic Regulation of Genes in a Mouse Model of Neuropathic Pain.

Clinical and animal studies have shown that acupuncture may benefit controlling neuropathic pain. However, the underlying molecular mechanisms are poorly understood. In a well-established mouse unilateral tibial nerve injury (TNI) model, we confirmed the efficacy of electroacupuncture (EA) in reducing mechanical allodynia and measured methylation and hydroxy-methylation levels in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC), two cortical regions critically involved in pain processing. TNI resulted in increased DNA methylation of both the contra- and ipsilateral S1, while EA only reduced contralateral S1 methylation. RNA sequencing of the S1 and ACC identified differentially expressed genes related to energy metabolism, inflammation, synapse function, and neural plasticity and repair. One week of daily EA decreased or increased the majority of up- or downregulated genes, respectively, in both cortical regions. Validations of two greatly regulated genes with immunofluorescent staining revealed an increased expression of gephyrin in the ipsilateral S1 after TNI was decreased by EA; while TNI-induced increases in Tomm20, a biomarker of mitochondria, in the contralateral ACC were further enhanced after EA. We concluded that neuropathic pain is associated with differential epigenetic regulations of gene expression in the ACC and S1 and that the analgesic effect of EA may involve regulating cortical gene expression.

Consideration for Limb Salvage in Place of Amputation in Complex Tibial Fracture With Neurovascular Injury: A Case Report.

High-energy tibial fractures often present with associated soft tissue injuries, including neuro-vascular damage, complicating the treatment decision. A 33-year-old male presented with Gustilo Anderson type IIIA fracture of the left distal tibia and fibula with associated closed calcaneus fracture and tibial nerve transection. Amputation was discussed, but the decision was made for limb salvage with nerve allograft. The patient displayed satisfactory functional recovery at 29 months postoperatively without need for major revision, grafting, arthrodesis, or amputation. This case report provides an example of successful limb salvage utilizing tibial nerve allograft in a complex high-energy lower extremity injury. Level of Evidence: IV.

Defects of the sciatic nerve and its divisions treated by direct suturing in 90 degrees knee flexion: report on the first clinical series.

OBJECTIVE: To evaluate functional results after treatment of large defects of the sciatic nerve and its divisions by direct nerve suturing in high knee flexion. METHODS: A retrospective review was conducted in patients treated for lower extremity nerve defects between 2011 and 2019. Inclusion criteria were a defect > 2 cm with a minimal follow-up period of 2 years for the sciatic nerve and 1 year for its divisions. Nerve defects were bridged by an end-to-end suture with the knee flexed at 90° for 6 weeks. Functional results were assessed based on the Medical Research Council's grading system. RESULTS: Seventeen patients with a mean age of 27.6 years were included. They presented with seven sciatic nerve defects and ten division defects, including eight missile injuries. The mean time to surgery was 12.3 weeks and the mean nerve defect length was 5 cm. Overall, 21 nerve sutures were performed, with eight in the tibial distribution and 13 in the fibular distribution. Post-operatively, there was no significant knee stiffness related to the immobilization. The mean follow-up time was 24.5 months. Meaningful motor and sensory recovery were observed after 7 of 8 sutures in the tibial distribution and 11 of 13 sutures in the fibular distribution. A functional sural triceps muscle with protective sensibility of the sole was restored in all patients. There were no differences according to the injury mechanisms. CONCLUSION: Temporary knee flexion at 90° allows for direct coaptation of sciatic nerve defects up to 8 cm, with promising results no matter the level or mechanism of injury.

MiR-463-3p inhibits tibial nerve regeneration via post-transcriptional suppression of SPRR1A.

Background: miRNAs have been involved in neural development, degeneration, and regeneration. MiR-463-3p is expressed in reproductive and nervous systems. In this study, the role of miR-463-3p in tibial nerve injury and regeneration was explored. Materials and methods: A model of tibial nerve injury was established with the crush method, and the levels of miR-463-3p were detected at days 0, 3, 7, 12, 18 and 24 post-injury. Then, primary tibial nerve cells were isolated from newborn mice, and miR-463-3p was respectively overexpressed and knocked down in cultured cells. Behaviors of tibial nerve cells were detected. Furthermore, bioinformatics technology was used to investigate the underlying mechanism. Results: The expression miR-463-3p was robustly increased in the injured tibial nerve in vivo and in tibial nerve cells treated with oxygen-glucose deprivation. The data on gain- and loss-of-function demonstrated that miR-463-3p negatively regulated including neurite length, percentage of cells with neurites, and cell branching in tibial nerve cells. Small proline-rich repeat protein 1 A (SPRR1A), an identified nerve regeneration associated genes, was identified as a target gene of miR-463-3p. Conclusion: Inhibition of miR-463-3p could increase SPRR1A expression in the tibial nerve tissue and improve regeneration of the tibial nerve post-injury in vivo.

Rate of Neurologic Injury Following Lateralizing Calcaneal Osteotomy Performed Through a Medial Approach.

BACKGROUND: Calcaneal osteotomies are commonly used to correct varus hindfoot alignment in patients with symptomatic cavovarus deformity. Translational, closing wedge, and Malerba-type osteotomies have been implicated in the development of tarsal tunnel syndrome and neurologic injury to branches of the tibial nerve. The authors hypothesized that there would be minimal clinically important injury to the tibial nerve by performing a translational calcaneal osteotomy from a medial approach. METHODS: All patients undergoing a cavovarus reconstruction by a single surgeon were identified. Patients were included if they underwent a lateralizing calcaneal osteotomy via medial approach. Demographics, operative reports, and clinic notes were reviewed to identify concomitant procedures performed, incidence of postoperative tarsal tunnel syndrome, complications, and preoperative and postoperative nerve examinations. Postoperative radiographs were reviewed for location of the osteotomy relative to the posterior tubercle. RESULTS: Twenty-four patients underwent lateralizing calcaneal osteotomy via a medial approach. Of the osteotomies, 83.3% (20/24) were in the middle third of the calcaneus, with a mean of 11.6-mm translation. No patients developed postoperative tarsal tunnel syndrome or tibial nerve palsy. CONCLUSION: Lateralizing calcaneal osteotomy performed via a medial approach had a clinically negligible incidence of neurologic injury. Adequate translation was achieved to obtain correction of varus hindfoot deformity. The authors believe that there is less direct and less percussive injury to branches of the tibial nerve when performing the osteotomy from medial to lateral. This technique may represent an operative strategy to minimize risk to the tibial nerve and reduce neurologic deficit following cavovarus reconstruction. LEVEL OF EVIDENCE: Level IV, case series.

Inhibition of neuropathic hyperalgesia by intrathecal bone marrow stromal cells is associated with alteration of multiple soluble factors in cerebrospinal fluid.

Injury-induced neuropathic pain remains a serious clinical problem. Recent studies indicate that bone marrow stromal cells (BMSCs) effectively attenuate chronic neuropathic pain in animal models. Here, we examined the therapeutic effect of intrathecal administration of BMSCs isolated from young (1-month-old) rats on pain hypersensitivity induced by tibial nerve injury. Cerebrospinal fluid (CSF) was collected and analyzed to examine the effect of BMSC administration on the expression of 67 soluble factors in CSF. A sustained remission in injury-induced mechanical hyperalgesia was observed in BMSC-treated rats but not in control animals. Engrafted BMSCs were observed in spinal cords and dorsal root ganglia at 5 weeks after cell injection. Injury significantly decreased the levels of six soluble factors in CSF: intercellular adhesion molecule 1 (ICAM-1), interleukin-1ß (IL-1ß), IL-10, hepatocyte growth factor (HGF), Nope protein, and neurogenic locus notch homolog protein 1 (Notch-1). Intrathecal BMSCs significantly attenuated the injury-induced reduction of ICAM-1, IL-1ß, HGF, IL-10, and Nope. This study adds to evidence supporting the use of intrathecal BMSCs in pain control and shows that this effect is accompanied by the reversal of injury-induced reduction of multiple CSF soluble factors. Our findings suggest that these soluble factors may be potential targets for treating chronic pain.

Challenging the catechism of therapeutics for chronic neuropathic pain: Targeting CaV2.2 interactions with CRMP2 peptides.

Chronic neuropathic pain management is a worldwide concern. Pharmaceutical companies globally have historically targeted ion channels as the therapeutic catechism with many blockbuster successes. Remarkably, no new pain therapeutic has been approved by European or American regulatory agencies over the last decade. This article will provide an overview of an alternative approach to ion channel drug discovery: targeting regulators of ion channels, specifically focusing on voltage-gated calcium channels. We will highlight the discovery of an anti-nociceptive peptide derived from a novel calcium channel interacting partner - the collapsin response mediator protein 2 (CRMP2). In vivo administration of this peptide reduces pain behavior in a number of models of neuropathic pain without affecting sympathetic-associated cardiovascular activity, memory retrieval, sensorimotor function, or depression. A CRMP2-derived peptide analgesic, with restricted access to the CNS, represents a completely novel approach to the treatment of severe pain with an improved safety profile. As peptides now represent one of the fastest growing classes of new drugs, it is expected that peptide targeting of protein interactions within the calcium channel complex may be a paradigm shift in ion channel drug discovery.

The effects of vitamin B12 and diclofenac and their combination on cold and mechanical allodynia in a neuropathic pain model in rats.

The present study was performed to investigate the effects of long-term intraperitoneal (IP) injection of vitamin B12 and diclofenac in separate and combined treatments on cold and mechanical allodynia in a neuropathic pain model in rats. Neuropathic pain was induced by crush injury in right tibial nerve. Acetone spray and von Frey tests were used to obtain cold and mechanical allodynia responses, respectively, on day 11 after nerve crush. Normal saline, vitamin B12 and diclofenac were injected intraperitoneally for 10 consecutive days after surgery. Normal saline treated rats showed cold and mechanical allodynia responses after nerve crush. Vitamin B12 at doses of 50, 100 and 200 µg kg(-1) and diclofenac at a dose of 2 mg kg(-1) produced antiallodynic effects. Antiallodynic effects were not observed when subanalgesic doses of vitamin B12 (25 µg kg(-1)) and diclofenac (0.25 mg kg(-1)) were used together. By increasing the dose of vitamin B12 to an effective dose (100 µg kg(-1)), antiallodynic effects were observed when compared with diclofenac (0.25 mg kg(-1)) alone. The results indicated that vitamin B12 and diclofenac produced neuropathic pain suppressing effects. Moreover, a potentiation effect was observed between vitamin B12 and diclofenac.