Regenerative Peripheral Nerve Interface: Surgical Protocol for a Randomized Controlled Trial in Postamputation Pain.

Surgical procedures, including nerve reconstruction and end-organ muscle reinnervation, have become more prominent in the prosthetic field over the past decade. Primarily developed to increase the functionality of prosthetic limbs, these surgical procedures have also been found to reduce postamputation neuropathic pain. Today, some of these procedures are performed more frequently for the management and prevention of postamputation pain than for prosthetic fitting, indicating a significant need for effective solutions to postamputation pain. One notable emerging procedure in this context is the Regenerative Peripheral Nerve Interface (RPNI). RPNI surgery involves an operative approach that entails splitting the nerve end longitudinally into its main fascicles and implanting these fascicles within free denervated and devascularized muscle grafts. The RPNI procedure takes a proactive stance in addressing freshly cut nerve endings, facilitating painful neuroma prevention and treatment by enabling the nerve to regenerate and innervate an end organ, i.e., the free muscle graft. Retrospective studies have shown RPNI's effectiveness in alleviating postamputation pain and preventing the formation of painful neuromas. The increasing frequency of utilization of this approach has also given rise to variations in the technique. This article aims to provide a step-by-step description of the RPNI procedure, which will serve as the standardized procedure employed in an international, randomized controlled trial (ClinicalTrials.gov, NCT05009394). In this trial, RPNI is compared to two other surgical procedures for postamputation pain management, specifically, Targeted Muscle Reinnervation (TMR) and neuroma excision coupled with intra-muscular transposition and burying.

Targeted Muscle Reinnervation: Surgical Protocol for a Randomized Controlled Trial in Postamputation Pain.

Over the past decade, the field of prosthetics has witnessed significant progress, particularly in the development of surgical techniques to enhance the functionality of prosthetic limbs. Notably, novel surgical interventions have had an additional positive outcome, as individuals with amputations have reported neuropathic pain relief after undergoing such procedures. Subsequently, surgical techniques have gained increased prominence in the treatment of postamputation pain, including one such surgical advancement - targeted muscle reinnervation (TMR). TMR involves a surgical approach that reroutes severed nerves as a type of nerve transfer to "target" motor nerves and their accompanying motor end plates within nearby muscles. This technique originally aimed to create new myoelectric sites for amplified electromyography (EMG) signals to enhance prosthetic intuitive control. Subsequent work showed that TMR also could prevent the formation of painful neuromas as well as reduce postamputation neuropathic pain (e.g., Residual and Phantom Limb Pain). Indeed, multiple studies have demonstrated TMR's effectiveness in mitigating postamputation pain as well as improving prosthetic functional outcomes. However, technical variations in the procedure have been identified as it is adopted by clinics worldwide. The purpose of this article is to provide a detailed step-by-step description of the TMR procedure, serving as the foundation for an international, randomized controlled trial (ClinicalTrials.gov, NCT05009394), including nine clinics in seven countries. In this trial, TMR and two other surgical techniques for managing postamputation pain will be evaluated.

Surgical treatments for postamputation pain: study protocol for an international, double-blind, randomised controlled trial.

BACKGROUND: Painful conditions such as residual limb pain (RLP) and phantom limb pain (PLP) can manifest after amputation. The mechanisms underlying such postamputation pains are diverse and should be addressed accordingly. Different surgical treatment methods have shown potential for alleviating RLP due to neuroma formation - commonly known as neuroma pain - and to a lesser degree PLP. Two reconstructive surgical interventions, namely targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI), are gaining popularity in postamputation pain treatment with promising results. However, these two methods have not been directly compared in a randomised controlled trial (RCT). Here, we present a study protocol for an international, double-blind, RCT to assess the effectiveness of TMR, RPNI, and a non-reconstructive procedure called neuroma transposition (active control) in alleviating RLP, neuroma pain, and PLP. METHODS: One hundred ten upper and lower limb amputees suffering from RLP will be recruited and assigned randomly to one of the surgical interventions (TMR, RPNI, or neuroma transposition) in an equal allocation ratio. Complete evaluations will be performed during a baseline period prior to the surgical intervention, and follow-ups will be conducted in short term (1, 3, 6, and 12 months post-surgery) and in long term (2 and 4 years post-surgery). After the 12-month follow-up, the study will be unblinded for the evaluator and the participants. If the participant is unsatisfied with the outcome of the treatment at that time, further treatment including one of the other procedures will be discussed in consultation with the clinical investigator at that site. DISCUSSION: A double-blind RCT is necessary for the establishment of evidence-based procedures, hence the motivation for this work. In addition, studies on pain are challenging due to the subjectivity of the experience and the lack of objective evaluation methods. Here, we mitigate this problem by including different pain evaluation methods known to have clinical relevance. We plan to analyse the primary variable, mean change in NRS (0-10) between baseline and the 12-month follow-up, using the intention-to-treat (ITT) approach to minimise bias and keep the advantage of randomisation. The secondary outcomes will be analysed on both ITT and per-protocol (PP). An adherence protocol (PP population) analysis will be used for estimating a more realistic effect of treatment. TRIAL REGISTRATION: ClincialTrials.gov NCT05009394.

Effect of magnification in pediatric liver transplantation: A systematic review and meta-analysis.

BACKGROUND: Hepatic artery thrombosis (HAT) represents a devastating and often fatal complication of liver transplantation. Due to the small vessel caliber in pediatric patients, the use of an operating microscope has largely become the standard for hepatic artery reconstruction to reduce the rate of HAT. Recent evidence, however, suggests that loupe magnification for anastomosis may be equally effective. We aimed to determine the effect of magnification on the rate of hepatic artery thrombosis in pediatric liver transplantation. METHODS: A systematic search of the literature was conducted. Thousand eighty-eight unique titles were assessed by two independent reviewers. Studies directly comparing rates of HAT from loupe magnification and operating microscope-assisted anastomoses were eligible for meta-analysis. RESULTS: Among primary transplants, the rate of HAT was 6.0%. Operating microscope anastomosis was associated with a 2.6% decrease in the rate of HAT compared to that of loupe magnification (4.9% and 7.4%, respectively, p < .040). When re-transplants were included, the rate of HAT was 5.8%. Operating microscope anastomosis was associated with a 1.0% decrease in the rate of HAT compared to that of loupe magnification (5.3% and 6.3%, respectively, p < .279). Meta-analysis of eligible studies demonstrated a reduction in the rate of HAT with the use of an operating microscope (p < .03). CONCLUSIONS: Anastomosis under an operating microscope may be associated with decreased rates of HAT in children undergoing primary liver transplantation. Further high-quality studies comparing the two techniques are needed.

Breast Equalization Augmentation: The Use of Ultrasonic Assisted Liposuction for Correction of Primary Breast Asymmetry with Bilateral Augmentation.

BACKGROUND: The purpose of this study was to determine the effectiveness of using ultrasonic assisted liposuction (UAL) to achieve sufficient breast symmetry allowing for the use of same sized implants in patients presenting for elective breast augmentation surgery. METHODS: A retrospective review was performed of patients presenting for augmentation mammoplasty with breast asymmetry who underwent ultrasonic assisted liposuction in combination with implant augmentation. Pre-operative differences in breast volumes were determined using water displacement, and these measurements were compared to final lipoaspirates required to achieve symmetry. To estimate the volume of lipoaspirate required, we suggested to aim for twice the volume difference obtained by water displacement. The success of the procedure was measured by the ability to use the same size implants bilaterally. RESULTS: A total of 35 patients were included in this review. In 85% of patients, UAL was sufficient to permit the use of equally sized implants bilaterally. However, when different sized implants were required, the size difference between implants was not greater than 25 cc. The UAL was also effective in correcting minor ptosis and nipple position. The main observed disadvantage was prolonged bruising and swelling. CONCLUSION: The use of UAL for correction of primary breast asymmetry with bilateral breast augmentation allows balancing of breast tissue volumes and the use of same size implants and eliminates the need for balancing mastopexy procedures. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

The Transition to Microsurgical Technique for Hepatic Artery Reconstruction in Pediatric Liver Transplantation.

BACKGROUND: Hepatic artery thrombosis represents a potentially fatal complication following liver transplantation. Rates of hepatic artery thrombosis are significantly higher in children, with mortality reported up to 80 percent. Microsurgical anastomosis has been shown to decrease the rate of hepatic artery thrombosis and now represents the standard of care at the authors' institution. In this article, the authors present the largest study of its type directly comparing rates of hepatic artery thrombosis with and without microsurgical reconstruction of the hepatic artery. METHODS: All pediatric patients who underwent primary orthotopic liver transplantation between 1989 and 2018 were included. Patients were divided into two cohorts: standard anastomosis with loupes, and microsurgical anastomosis under the operating microscope. The authors' primary outcome was the rate of hepatic artery thrombosis. Secondary outcomes were graft survival, patient survival, retransplantation rate, requirement for intraoperative blood products, and length of stay. RESULTS: Two hundred thirty-one children met criteria for inclusion. One hundred eighty cases were performed with loupe magnification and 51 cases were performed under the microscope. The hepatic artery thrombosis rate was lower, but not significantly so (p = 0.114), in the microsurgical group [n = 1 (2.0 percent)] compared with the standard cohort [n = 15 (8.3 percent)]. Survival analysis revealed a significant increase in graft survival with microsurgical anastomosis (p = 0.020), but not patient survival (p = 0.196). The retransplantation rate was significantly lower with microsurgical anastomosis (p = 0.021). CONCLUSIONS: Microsurgical anastomosis was associated with a clinically important decrease in hepatic artery thrombosis compared with standard loupe anastomosis. The graft survival rate was significantly higher in the microsurgical cohort, with a reduced retransplantation rate at 1 year. On this basis, the authors recommend microsurgical hepatic artery anastomosis in cases of pediatric liver transplantation. . CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Association of intraneural perineurioma with neurofibromatosis type 2.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by mutations of the NF2 tumor suppressor gene that predisposes patients to develop multiple tumors in the peripheral and central nervous system. The most common neoplasms associated with the disease are schwannomas and meningiomas. Both have been shown to contain abnormalities in chromosome 22 and the NF2 gene, suggesting a genetic component to their pathogenesis. Perineuriomas are rare benign tumors arising from the perineural cells. They are commonly classified as intraneural and soft tissue perineuriomas. Several studies have reported mutations in genes on chromosome 22 in both types of perineuriomas, and there are reports of soft tissue perineuriomas associated with NF2 gene mutations. Despite this, perineuriomas are not considered as part of the NF2 constellation of tumors. METHOD: The electronic medical records were searched for patients with a radiologic or pathologic diagnosis of intraneural perineurioma. Patients with clinical signs and genetic testing consistent with a diagnosis of NF2 were further evaluated. RESULTS: Of 112 patients meeting inclusion criteria, there were two cases of intraneural perineurioma in patients with NF2 treated at our institution (1.8%). We include a third patient treated at another facility for whom we performed a virtual consultation. CONCLUSIONS: The rarity of both NF2 and perineuriomas could explain the rarity of perineuriomas in the setting of NF2. Furthermore, there is divergent intraneural and soft tissue perineurioma somatic mutation pathogenesis, and there may be cytogenetic overlap between perineuriomas and multiple tumor syndromes. Our observed occurrence of intraneural perineurioma in the setting of NF2 in several patients provides further evidence of a potential link between the NF2 gene and the development of intraneural perineurioma.

The Utility and Efficiency of a Resident Hand Clinic for the Management of Acute Hand Trauma at the University of Alberta.

BACKGROUND: The University of Alberta established a resident-run hand clinic in 2005 to expeditiously manage the growing numbers of patients with traumatic hand injuries. The purpose of this study was to examine the clinical volume and types of cases assessed and treated in the clinic, as well as gauge patient satisfaction with care received. METHODS: A retrospective chart review and patient satisfaction questionnaire were conducted for patients assessed in the hand clinic in 2015. Demographic data, referral data, and treatment required were recorded. Patients were asked to complete a survey on their experience at the end of their visit. RESULTS: A total of 1022 charts were reviewed. The most common reason for referral was a fracture or dislocation (57%), followed by tendon injury (18%). The average wait time to be seen in clinic was 2.97 ± 2.13 days in the winter and 4.12 ± 2.14 days in the summer. Forty-seven percent of patients required splinting, 17% required a procedure, and 21% of patients were referred for surgery. Patient satisfaction on average was 9.29 ± 0.87 on a satisfaction scale of 10. CONCLUSION: In a 6-month period, residents attending hand clinic assessed and treated 1022 patients, providing timely management of acute injuries. A resident-run hand clinic is an effective model to decrease wait times for patients, to decrease time spent assessing nonemergent injuries in the emergency department, and to concentrate hand trauma in a setting conducive to resident training, while still maintaining high patient satisfaction.

HISTORIQUE: En 2005, l'université de l'Alberta a mis sur pied une clinique de la main dirigée par des résidents pour accélérer la prise en charge du nombre croissant de patients ayant des lésions traumatiques des mains. La présente étude visait à examiner le volume clinique et le type de cas évalués et traités en clinique, ainsi qu'à évaluer la satisfaction des patients à l'égard des soins reçus. MÉTHODOLOGIE: Les chercheurs ont procédé à une analyse rétrospective des dossiers et ont distribué un questionnaire sur la satisfaction des patients qui avaient été évalués dans la clinique de la main en 2015. Ils ont consigné les données démographiques, les données sur l'envoi vers un médecin et le traitement requis. Les patients ont été invités à remplir un sondage sur leur expérience à la fin de leur rendez-vous. RÉSULTATS: Au total, les chercheurs ont examiné 1 022 dossiers. La principale raison de l'orientation vers un médecin était une fracture ou une dislocation (57 %), suivie d'une lésion du tendon (18 %). Le temps d'attente moyen pour être vu en clinique était de 2,97 ± 2,13 jours pendant l'hiver et de 4,12 ± 2,14 jours pendant l'été. De plus, 47 % des patients ont eu besoin d'une attelle, 17 % ont eu besoin d'une intervention et 21 % des patients ont été envoyés en chirurgie. En moyenne, la satisfaction des patients était de 9,29 ± 0,87 sur une échelle de satisfaction de 10. CONCLUSION: Sur une période de six mois, les résidents qui ont travaillé à la clinique de la main ont évalué et traité 1 022 patients, assurant une prise en charge rapide des lésions aiguës. Une clinique de la main dirigée par des résidents est un modèle efficace pour réduire les temps d'attente pour les patients, réduire le temps passé à évaluer des blessures non urgentes à l'urgence et concentrer les traumatismes de la main dans un milieu favorable à la formation des résidents tout en assurant une satisfaction élevée des patients.

Brief electrical stimulation improves nerve regeneration after delayed repair in Sprague Dawley rats.

Functional recovery after peripheral nerve injury and surgical repair declines with time and distance because the injured neurons without target contacts (chronic axotomy) progressively lose their regenerative capacity and chronically denervated Schwann cells (SCs) atrophy and fail to support axon regeneration. Findings that brief low frequency electrical stimulation (ES) accelerates axon outgrowth and muscle reinnervation after immediate nerve surgery in rats and human patients suggest that ES might improve regeneration after delayed nerve repair. To test this hypothesis, common peroneal (CP) neurons were chronically axotomized and/or tibial (TIB) SCs and ankle extensor muscles were chronically denervated by transection and ligation in rats. The CP and TIB nerves were cross-sutured after three months and subjected to either sham or one hour 20Hz ES. Using retrograde tracing, we found that ES significantly increased the numbers of both motor and sensory neurons that regenerated their axons after a three month period of chronic CP axotomy and/or chronic TIB SC denervation. Muscle and motor unit forces recorded to determine the numbers of neurons that reinnervated gastrocnemius muscle demonstrated that ES significantly increased the numbers of motoneurons that reinnervated chronically denervated muscles. We conclude that electrical stimulation of chronically axotomized motor and sensory neurons is effective in accelerating axon outgrowth into chronically denervated nerve stumps and improving target reinnervation after delayed nerve repair. Possible mechanisms for the efficacy of ES in promoting axon regeneration and target reinnervation after delayed nerve repair include the upregulation of neurotrophic factors.

Mapping sensory nerve communications between peripheral nerve territories.

The human cutaneous sensory map has been a work in progress over the past century, depicting sensory territories supplied by both the spinal and cranial nerves. Two critical discoveries, which shaped our understanding of cutaneous innervation, were sensory dermatome overlap between contiguous spinal levels and axial lines across areas where no sensory overlap exists. These concepts define current dermatome maps. We wondered whether the overlap between contiguous sensory territories was even tighter: if neural communications were present in the peripheral nerve territories consistently connecting contiguous spinal levels? A literature search using peer-reviewed articles and established anatomy texts was performed aimed at identifying the presence of communications between sensory nerves in peripheral nerve territories and their relationship to areas of adjacent and non-adjacent spinal or cranial nerves and axial lines (lines of discontinuity) in the upper and lower limbs, trunk and perineum, and head and neck regions. Our findings demonstrate the consistent presence of sensory nerve communications between peripheral nerve territories derived from spinal nerves within areas of axial lines in the upper and lower limbs, trunk and perineum, and head and neck. We did not find examples of communications crossing axial lines in the limbs or lines of discontinuity in the face, but did find examples crossing axial lines in the trunk and perineum. Sensory nerve communications are common. They unify concepts of cutaneous innervation territories and their boundaries, and refine our understanding of the sensory map of the human skin.

Distal nerve transfers are effective in treating patients with upper trunk obstetrical brachial plexus injuries: an early experience.

BACKGROUND: Current surgical management of obstetrical brachial plexus injury is primary reconstruction with sural nerve grafts. Recently, the nerve-to-nerve transfer technique has been used to treat brachial plexus injury in adults, affording the benefit of distal coaptations that minimize regenerative distance. The purpose of this study was to test the hypothesis that nerve transfers are effective in reconstructing isolated upper trunk obstetrical brachial plexus injuries. METHODS: Ten patients aged 10 to 18 months were treated with three nerve transfers: spinal accessory nerve to the suprascapular nerve for shoulder abduction and external rotation; a radial to axillary nerve for shoulder abduction; and ulnar or median nerve transfer to the musculocutaneous nerve for elbow flexion. Patients were assessed preoperatively and postoperatively using the Active Movement Scale. All patients were followed regularly for up to 2 years. RESULTS: Improvement in elbow and shoulder function was observed between 6 and 24 months. By 6 months, all patients passed the cookie test. At 24 months, shoulder abduction improved from 3.7 ± 0.6 to 5.0 ± 0.5, shoulder external rotation from 1.8 ± 0.4 to 4.3 ± 0.6, shoulder flexion from 3.7 ± 0.5 to 5.4 ± 0.5, elbow flexion from 3.7 ± 0.6 to 6.3 ± 0.2, and forearm supination from 2.1 ± 0.4 to 5.9 ± 0.2. There was no clinically appreciable donor-site morbidity. CONCLUSIONS: Nerve transfers reduced operative times compared with traditional nerve grafting procedures. Those patients showed significant gains in Active Movement Scale score by 24 months postoperatively, comparable to results achieved by nerve grafting. These findings support nerve transfers as a potential alternative treatment option for upper trunk obstetrical brachial plexus injuries. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

MRI findings in patients with tibial nerve compression near the knee.

The soleus sling has been recently identified as a site of compression of the tibial nerve resulting in tibial neuropathy. Diagnosis of soleal sling syndrome is difficult, and has been based mainly on clinical examination. Advances in MR imaging with high-resolution 3-Tesla scanners have made direct visualization of nerve pathology possible. With the use of high-resolution imaging and fat-suppression protocols, tibial nerve compression at the soleal fascial arch can be demonstrated in a subset of patients presenting with idiopathic tibial neuropathy. The purpose of this paper is to confirm the ability of MR imaging to demonstrate pathologic changes in the tibial nerve in patients presenting with soleal sling syndrome. Additionally, patients presenting with tibial neuropathy and ganglion cysts, both extra- and intraneural, were examined to determine if the site of compression corresponded to the region of the soleus sling. Nine patients were included in the study, two with idiopathic soleus sling syndrome, four with extraneural, and three with intraneural ganglion cysts. In the patients presenting with idiopathic soleus sling syndrome, MR imaging demonstrated a thickened soleus sling with T2 hyperintensity of the tibial nerve at the level of the sling and denervation changes in muscles of the posterior compartment of the leg. In patients with extraneural ganglion cysts, MR imaging demonstrated a "sandwich"-like compression of the tibial nerve between the cyst and the soleus sling with corresponding tibial nerve T2 hyperintensity and denervation change in posterior compartment muscles. No compression of the tibial nerve at the soleus sling was found in the intraneural ganglion population. We conclude that MR imaging is effective in demonstrating pathologic changes in the tibial nerve at the soleus sling. Based on the MRI findings, we also believe that the soleus sling is a component of the compression when patients present with extraneural ganglion cysts and tibial neuropathy near the knee; in these patients, we recommend release of the soleus sling as part of the definitive management.

Unique occurrence of mucosa-associated lymphoid tissue lymphoma disseminated to peripheral nerves.

Lymphomatous spread to peripheral nerves is a rare but long recognized complication, most commonly involving aggressive B-cell lymphomas. A 67-year-old woman with a history of a low-grade, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, which was in remission, presented with a left-sided forearm mass and numbness over the dorsolateral aspect of the thumb. Magnetic resonance imaging revealed a mass associated with the superficial radial sensory nerve in the distal forearm, which demonstrated fluorodeoxyglucose avidity on positron emission tomography. An ultrasound-guided needle biopsy was performed yielding a diagnosis of low-grade lymphoma, consistent with extranodal marginal zone lymphoma. Subsequently, she was found to have bilateral sciatic nerve involvement. This case describes the first known reported spread of MALT lymphoma to peripheral nerves in the limbs.

Side-to-side nerve grafts sustain chronically denervated peripheral nerve pathways during axon regeneration and result in improved functional reinnervation.

BACKGROUND: Progressive atrophy of Schwann cells in denervated nerve stumps is a major reason for progressive failure of functional recovery after peripheral nerve injury and surgical repair. OBJECTIVE: To examine whether side-to-side nerve bridges between an intact donor nerve and a recipient denervated distal nerve stump promote nerve growth and in turn, protect distal nerve stumps to improve axon regeneration after delayed surgical repair. METHODS: In Sprague-Dawley rats, 1 or 3 side-to-side common peroneal (CP) nerve bridges were used to bridge between the donor intact tibial (TIB) nerve and a recipient denervated CP distal nerve stump in the contralateral hind limb. No bridges were placed in control animals. After 4 months, either a fluorescent retrograde dye was applied to back-label TIB motoneurons with axons that had grown into the CP nerve stump or the proximal and distal CP nerve stumps were resutured in experimental and control animals to encourage CP nerve regeneration for 5 months. Retrograde dyes were again applied to count CP motoneurons that regenerated their axons through protected and unprotected nerve stumps. RESULTS: Significantly more donor TIB motoneurons regenerated axons into the recipient denervated CP nerve stump through 3 side-to-side CP nerve bridges compared with 1 bridge. This TIB nerve protection significantly increased the number of CP motoneurons regenerating axons through the denervated CP nerve stumps, the number of regenerated axons, and the weight of the reinnervated muscles. CONCLUSION: Multiple side-to-side nerve bridges protect chronically denervated nerve stumps to improve axon regeneration and target reinnervation after delayed nerve repair.