Clinical and Medical Imaging Findings of the Forefoot Following a COVID-19 Infection: A Case Report.

Since the beginning of the SARS-CoV-2 pandemic, manifestations of the COVID-19 virus have been reported throughout the body, visible both clinically and radiographically. In the foot and ankle, one such phenomenon presents as cutaneous changes associated with neuralgia to the digits. Although rare, emerging reports described similar manifestations of COVID-19 in the foot, though limited to superficial structures. In this case report, we present a 52-year-old male experiencing burning pain and hyperpigmented lesions to the digits of his left foot 2 weeks prior to a formal diagnosis with COVID-19. Advanced imaging showed a third interspace neuroma as well as distal-to-proximal bone marrow edema in the distal phalanx of all digits, a pattern seen in vasculopathies, 4 weeks after diagnosis. In the absence of diabetes mellitus or peripheral vascular disease, the patient underwent a simple neurectomy. At the follow-up appointment 12 weeks after the initial encounter, his symptoms resolved. Our study reports a case describing osseous along with cutaneous manifestations in the foot of a patient with COVID-19.

Robot-assisted resection of ganglion cell neuroma with a diameter of 78 mm: A case report.

RATIONALE: Intrathoracic paragangliomas are typically found within the intricate posterior mediastinal region adjacent to the vertebrae, often presenting with substantial volume. Surgical excision of such tumors presents formidable challenges and is conventionally performed via open surgical procedures. PATIENT CONCERNS: In this report, we present the case of a 53-year-old female patient who presented with the discovery of a left intrathoracic mass during a routine physical examination approximately 1 month prior. She complained of chest tightness and chest pain. DIAGNOSES: She complained of chest tightness and chest pain. Magnetic resonance imaging of the chest and brachial plexus revealed a mass adjacent to the left upper lung hilum, measuring approximately 78 × 63 × 72 mm. The initial suspicion leaned towards a benign lesion. Notably, there was slight compression of the left first thoracic nerve root and mild compression of the middle and lower trunks of the left brachial plexus. Based on the morphological features of the tumor and imaging findings, we suspected its benign nature. INTERVENTIONS: We opted for robot-assisted thoracic surgery to resect the mediastinal tumor. OUTCOMES: Subsequent postoperative pathology confirmed the diagnosis as a paraganglioma. The patient did not experience any notable complications post-surgery, and a 6-month follow-up revealed no signs of recurrence. LESSONS: The successful application of the robot-assisted thoracic surgery surgical technique underscores its efficacy in minimally invasive resection of sizable intrathoracic tumors situated in the posterior mediastinum.

Outcome measures used in peripheral nerve surgery for symptomatic neuroma in upper extremity amputations: A scoping review.

Novel surgical treatments for painful neuromas are increasingly used, but determining which provides the greatest benefit has been difficult due to the inconsistent use of outcome measures. We mapped the current literature of outcome measures used to evaluate peripheral nerve surgery for the management of symptomatic neuromas in patients who underwent an adult-acquired upper extremity amputation (UEA). Medline, Embase, Cochrane, and CINAHL were searched for primary research written in the English language from inception to February 2023. The search yielded 1137 articles, of which 35 were included for final analysis. Studies varied in their assessment of pain, health-related quality of life (HRQOL), neurotrophic measures, psychological and sensorimotor function, highlighting a consensus on crucial domains but also revealing significant heterogeneity in the use and application of outcome measures among primary studies. Our findings highlight the need to establish common standards that reflect the best evidence and unique needs of the UEA population. This includes developing a core outcome set, utilizing multi-center trials, and maintaining flexibility to adapt to ongoing advancements in patient-reported outcome measures (PROMs) research.

Targeted Muscle Reinnervation for a Symptomatic Neuroma in a Traumatic Transmetatarsal Amputee: A Case Report.

CASE: An overall healthy 48-year-old man suffered a left foot mangled crush injury resulting in a post-transmetatarsal amputation and subsequently developing a painful neuroma on the plantar surface of the foot. To avoid the zone of injury, targeted muscle reinnervation was used to treat the neuroma by coapting the tibial nerve to the motor point of the flexor hallucis longus (FHL) muscle. At 1-year follow-up, the patient reported no pain at rest, returned to work, and could ambulate with an orthosis for 30 minutes. CONCLUSION: Rare tibial nerve coaptations to the FHL could serve as a treatment option for patients with neuromas in traumatic postmetatarsal amputation.

The neuroma map: A systematic review of the anatomic distribution, etiologies, and surgical treatment of painful traumatic neuromas.

BACKGROUND: This study analyzed all reported cases of painful traumatic neuromas to better understand their anatomic distribution, etiologies, and surgical treatment. METHODS: PubMed, Embase, Cochrane, and Web of Science were searched in October 2023 for articles describing painful traumatic neuromas. RESULTS: In total, 414 articles reporting 5,562 neuromas were included and categorized into head/neck, trunk, upper extremity, lower extremity, and autonomic nerves. Distribution was as follows: Head/neck: 83 articles reported on 393 neuromas (93.2% iatrogenic) most frequently involving the lingual (44.4%), cervical plexus (15.0%), great auricular (8.6%), inferior/superior alveolar (8.3%), and occipital (7.2%) nerves. Trunk: 47 articles reported on 552 neuromas (92.9% iatrogenic) most commonly involving the intercostal (40.0%), ilioinguinal (18.2%) and genitofemoral (16.2%) nerves. Upper extremity: 160 articles reported on 2082 neuromas (42.2% after amputation) most frequently involving the digital (47.0%), superficial radial (18.3%), and median (7.0%) nerves. Lower extremity: 128 articles reported on 2,531 neuromas (53.0% after amputation) most commonly involving the sural (17.9%), superficial peroneal (17.3%), and saphenous (16.0%) nerves. Autonomic nerves: 17 articles reported on 53 neuromas (100% iatrogenic) most frequently involving the biliary tract (64.2%) and vagus nerve (18.9%). Compared with the extremities, neuromas in the head/neck and trunk had significantly longer symptom duration before surgical treatment and the nerve end was significantly less frequently reconstructed after neuroma excision. CONCLUSION: Painful neuromas are predominantly reported in the extremities yet may occur throughout the body primarily after iatrogenic injury. Knowledge of their anatomic distribution from head to toe will encourage awareness to avoid injury and expedite diagnosis to prevent treatment delay.

A novel animal model of symptomatic neuroma for assessing neuropathic pain.

INTRODUCTION: Following amputation, peripheral nerves lack distal targets for regeneration, often resulting in symptomatic neuromas and debilitating neuropathic pain. Animal models can establish a practical method for symptomatic neuroma formation for better understanding of neuropathic pain pathophysiology through behavioral and histological assessments. We created a clinically translatable animal model of symptomatic neuroma to mimic neuropathic pain in patients and assess sexual differences in pain behaviors. METHODS: Twenty-two male and female rats were randomly assigned to one of two experimental groups: (1) neuroma surgery, or (2) sham surgery. For the neuroma experimental group, the tibial nerve was transected in the thigh, and the proximal segment was placed under the skin for mechanical testing at the site of neuroma. For the sham surgery, rats underwent tibial nerve isolation without transection. Behavioral testing consisted of neuroma-site pain, mechanical allodynia, cold allodynia, and thermal hyperalgesia at baseline, and then weekly over 8 weeks. RESULTS: Male and female neuroma rats demonstrated significantly higher neuroma-site pain response compared to sham groups starting at weeks 3 and 4, indicating symptomatic neuroma formation. Weekly assessment of mechanical and cold allodynia among neuroma groups showed a significant difference in pain behavior compared to sham groups (p < 0.001). Overall, males and females did not display significant differences in their pain responses. Histology revealed a characteristic neuroma bulb at week 8, including disorganized axons, fibrotic tissue, Schwann cell displacement, and immune cell infiltration. CONCLUSION: This novel animal model is a useful tool to investigate underlying mechanisms of neuroma formation and neuropathic pain.

Frequency and Localization of Neuromas in Transtibial Residual Limbs.

OBJECTIVE: To describe the frequency and localization of neuromas in residual limbs of individuals with transtibial amputation using ultrasound imaging. DESIGN: Cross-sectional study. SETTING: Rehabilitation center research laboratory. PARTICIPANTS: Adults who have lived with a transtibial amputation for >12 months were recruited for this study. Participants were included regardless of the presence or absence of residual limb neuropathic pain. Twenty-three participants (24 transtibial residual limbs) with and without residual limb neuropathic pain were enrolled. The etiology of amputation of most participants was peripheral vascular disease and diabetes. INTERVENTION: A comprehensive history was collected and a musculoskeletal ultrasound assessment for the presence and location of neuromas in their residual limb was conducted. During the ultrasound evaluation, a sonopalpation Tinel test was performed by applying pressure on each neuroma with the probe. MAIN OUTCOME MEASURES: Number of neuromas and their localization in each residual limb examined. RESULTS: A total of 31 neuromas in the 24 transtibial residual limbs were identified by ultrasound imaging. The average number of neuromas per residual limb was 1.3. All the major peripheral nerves studied could present neuromas, with a predominance of the superficial fibular nerve within our sample. Thirty-five percent of all the neuromas were described as painful. CONCLUSIONS: The presence of terminal neuromas on surgically sectioned nerves in transtibial residual limbs is frequent. Seventy-nine percent of participants had at least one neuroma. Ultrasound imaging is clinically useful to identify neuromas. The evaluator can easily communicate with the patient to diagnose symptomatic neuromas.

Targeted Muscle Reinnervation: Factors Predisposing to Successful Pain Score Reduction.

BACKGROUND: Targeted muscle reinnervation (TMR) has demonstrated efficacy in reducing neuroma and chronic pain. In this article, we investigated postoperative outcomes in our patient cohort, with a focus on the role of nonmodifiable factors such as patient age and gender. METHODS: Patients who had extremity TMR from April 2018 to October 2022 were reviewed. Outcomes of interest included patient age, gender, cause and type of amputation, delayed versus immediate TMR, as well as postoperative improvement in pain as assessed by numerical rating score (NRS). RESULTS: A total of 40 patients underwent TMR on 47 limbs. Mean age was 46.2 ± 17.0 years. Delayed TMR (27, 57.4%) was most commonly performed, followed by immediate and delayed-immediate at 11 (23.4%) and 9 (19.1%), respectively. Amputation level was most commonly above-knee in 20 (42.6%) patients, followed by below-knee (12, 25.5%), transhumeral (8, 17.0%), transradial (6, 12.8%), and shoulder (1, 2.1%). The median time interval between amputation and TMR was 12 months. The median preoperative NRS assessing residual limb pain (RLP) for patients who underwent delayed TMR was 10. The median postoperative NRS assessing RLP for all patients was 0 (interquartile range25-75: 0-5) and significantly improved compared with preoperative NRS (P < 0.001). At the last follow-up for limbs that had delayed and delayed-immediate TMR (n = 36), 33 (91.7%) limbs had more than 50% resolution of RLP. There was a significant difference in median postoperative NRS by gender (4 in men and 0 in women) (P < 0.05). Postoperative median NRS also favored younger patients (0, <50 years compared with 4.5, >50 years) (P < 0.05). Multiple linear regression analysis showed that, of different variables analyzed, only male gender and older age were predictive of poorer postoperative outcomes. CONCLUSION: TMR showed high efficacy in our cohort, with improved short-term outcomes in women and younger patients.

Management of an Early-Onset, Painful Tibial Nerve Neuroma Using an Autologous Nerve Graft.

This case report describes the treatment of a postoperative painful neuroma of the tibial nerve using an autologous nerve graft in a dog. The patient presented with sudden non-weight-bearing lameness 10 days after iatrogenic tibial nerve injury during preparation of a reverse saphenous conduit flap. The dog showed severe pain at the surgical site without nerve deficits. A magnetic resonance imaging examination revealed an enlarged tibial nerve at the injury site, consistent with a neuroma. Analgesics were administered over 11 days, but the patient remained in severe pain and non-weight-bearing. Therefore, surgical resection was recommended. The fusiform neuroma was resected microsurgically, and a saphenous nerve graft was transplanted using an epineural nerve repair technique. Histopathological examination was consistent with a neuroma. The dog showed immediate pain relief and weight-bearing the day after surgery with normal motor function. The dog made a full recovery by the last follow-up 6 mo after surgery. If patients develop pain and lameness following surgery or nerve injury, neuroma formation must be considered, even shortly after surgery. Microsurgical resection and autologous nerve transplantation using an epineural nerve repair technique is a viable method to treat painful neuromas and minimize the risk for recurrence in dogs.

[Medical-surgical complications and their impact on patients' return to work whilst follow-up major lower-limb amputations in Hospital del Trabajador in Santiago (HTS)]. / Complicaciones médico-quirúrgicas y su impacto en el retorno laboral durante el seguimiento de pacientes con amputación mayor de extremidades inferiores en el Hospital del Trabajador de Santiago (HTS).

INTRODUCTION: The presence of different complications whilst follow-up amputee patients reaches 10-80%. The main objective of this research is to assess the impact of these in the return-to-work of lower-limb traumatic amputation cases. MATERIALS AND METHODS: A retrospective cohort research was carried out. Clinic-demographic variables information was recollected in order to assess its linkage to different medical-surgical complications and functional outcomes. Survival curves were created to evaluate the return-to-work of patients with and without complications. RESULTS: A total of 46 patients, on average aged 45.7 years old (91.3% men, 71.7% without comorbidities), were included on this research. The most frequent level of amputation was transtibial (65.2%). Residual limb pain, phantom pain, dermatological-infectious complications and painful neuroma were registered in 80.4%, 58.7%, 50% y 30.4% of the cases respectively. Half of the patients had returned to their workplace after 2years of post-surgical follow-up. The return-to-work rates were significantly lower in patients suffering from residual limb pain (p=0.0083) and from painful neuroma (p=0.0051). CONCLUSION: Complications are frequent during traumatic-amputee patients' follow-up and, some of them, may impact on the return-to-work rate.

Factors Associated With Symptom Recurrence After Surgical Treatment of Interdigital Neuroma: A Retrospective Chart Review of 127 Patients.

INTRODUCTION: Interdigital neuroma (IN) is a benign enlargement of tissue surrounding the common plantar digital nerve. Although the standard surgical treatment of IN remains debated, recent attention has been given to less-invasive surgical decompression by intermetatarsal ligament (IML) release with neurolysis. This study aimed to compare the outcomes of IML release with neurolysis with standard interdigital neurectomy. METHODS: A retrospective chart review was conducted on 350 consecutive patients who underwent surgical treatment of IN. Patients who satisfied our inclusion and exclusion criteria were categorized into two groups based on the surgical treatment received: IML release with neurolysis or interdigital neurectomy. Outcomes assessed included recurrence of symptoms, rate of revision surgery, and postoperative wound infection. RESULTS: Of the total sample, 40 patients (31.5%) reported recurrence of symptoms within a 12-month follow-up period. Patients who underwent IML release with neurolysis had a markedly higher recurrence rate (47.50%) than those who underwent interdigital neurectomy (24.14%). The rate of postoperative wound infection was similar between the two groups. Binary logistic regression revealed that only the surgical technique was associated with the recurrence of symptoms. Despite the higher rate of symptom recurrence in the IML release with neurolysis patient group, the rate of revision surgery in those with symptom recurrence was similar between both groups. DISCUSSION: IML release with neurolysis seems to have a higher risk of symptom recurrence than interdigital neurectomy. No patient-specific factors were identified as being associated with symptom recurrence. However, patients who did experience symptom recurrence in either surgical group had similar rates of revision surgery, which may be due to mild recurrent symptom severity in the IML release group that does not warrant revision surgery in these patients. Future studies should consider objective symptom recurrence severity and patient satisfaction. LEVEL OF EVIDENCE: Level III.

Active nerve management for above the knee amputation: A comparison of through the wound versus posterior approach.

Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) are used to prevent or treat neuromas in amputees. TMR for above-the-knee amputation (AKA) is most commonly performed through a posterior incision rather than the stump wound because recipient motor nerves are primarily located in the proximal third of the thigh. When preventative TMR is performed with concurrent AKA, a posterior approach requires intraoperative repositioning and an additional incision. The purpose of this study was to evaluate feasibility of TMR and operative times for nerve management performed through the wound compared to a posterior approach in AKA patients to guide surgical decision-making. Patients who underwent AKA with TMR between 2018-2023 were reviewed. Patients were divided into two groups: TMR performed through the wound (Group I) and TMR performed through a posterior approach (Group II). If a nerve was unable to undergo coaptation for TMR due to the lack of suitable donor motor nerves, RPNI was performed. Eighteen patients underwent AKA with nerve management were included from Group I (8 patients) and Group II (10 patients). TMR coaptations performed on distinct nerves was 1.5 ± 0.5 in Group I compared to 2.6 ± 0.5 in Group II (p = 0.001). Operative time for Group I was 200.7 ± 33.4 min compared to 326.5 ± 37.1 min in Group II (p = 0.001). TMR performed through the wound following AKA requires less operative time than a posterior approach. However, since recipient motor nerves are not consistently found near the stump, RPNI may be required with TMR whereas the posterior approach allows for more TMR coaptations.

Superficial branch of the radial nerve regularly contains fibers from the lateral antebrachial cutaneous nerve: A role in neuroma treatment.

BACKGROUND: Many surgical strategies aim to treat the symptomatic neuroma of the superficial branch of the radial nerve (SBRN). It is still difficult to treat despite many attempts to reveal a reason for surgical treatment failure. The lateral antebrachial cutaneous nerve (LACN) is known to overlap and communicate with SBRN. Our study aims to determine the frequency of spreading of LACN fibers into SBRN branches through a microscopic dissection to predict where and how often LACN fibers may be involved in SBRN neuroma. METHODS: Eighty-seven cadaveric forearms were thoroughly dissected. The path of LACN fibers through the SBRN branching was ascertained using microscopic dissection. Distances between the interstyloid line and entry of LACN fibers into the SBRN and emerging and bifurcation points of the SBRN were measured. RESULTS: The LACN fibers joined the SBRN at a mean distance of 1.7 ± 2.5 cm proximal to the interstyloid line. The SBRN contained fibers from the LACN in 62% of cases. Most commonly, there were LACN fibers within the SBRN's third branch (59%), but they were also observed within the first branch, the second branch, and their common trunk (21%, 9.2%, and 22%, respectively). The lowest rate of the LACN fibers was found within the SBRN trunk (6.9%). CONCLUSION: The SBRN contains LACN fibers in almost 2/3 of the cases, therefore, the denervation of both nerves might be required to treat the neuroma. However, the method must be considered based on the particular clinical situation.

Surgical treatment of painful neuroma in amputated and non-amputated patients: does the level of neurotomy affect clinical outcomes?

PURPOSE: To compare the outcomes of distal neurotomy (DN) versus proximal neurotomy (PN) for the surgical management of painful neuromas in amputees and non-amputees, whether used in passive or active treatment. METHODS: A retrospective study was conducted on patients who underwent surgery for painful traumatic neuromas between 2019 and 2022. DN with neuroma excision was performed at the level of the injury or amputation. PN was performed using a separate proximal approach without neuroma excision. Outcomes included a Numerical Rating Scale (NRS) score and Patient-Reported Outcomes Measurement Information System (PROMIS) scores, as well as patients' subjective assessments. RESULTS: A total of 33 patients were included: 17 amputees and 16 non-amputees. They totalized 43 neuromas treated by DN in 21 cases and PN in 22 cases. At the median follow-up time of 13 months, there were significant decreases in all NRS and PROMIS scores in the whole series. The decrease in limb pain scores was not significantly different between groups, except for the decrease in pain interference and patient satisfaction which were higher in the DN group. Sub-group analyses found the same significant differences in amputees. Targeted muscle reinnervation (TMR) was associated with a higher decrease in PROMIS scores. CONCLUSION: DN seemed to give better results in amputees but there were confusing factors related to associated lesions. In other situations, the non-inferiority of PN was demonstrated. PN could be of interest for treating neuromas of superficial sensory nerves, for avoiding direct revision of a well-fitted stump and in conjunction with TMR.

Neuroma Analysis in Humans: Standardizing Sample Collection and Documentation.

INTRODUCTION: The biology of symptomatic neuromas is poorly understood, particularly the factors causing pain in human neuromas. Pain presence varies among and within individuals, with some having painful and nonpainful neuromas. To bridge these knowledge gaps, our group developed a protocol for assessing neuroma pain and collecting tissue for molecular analysis. This manuscript outlines our workflow and challenges and aims to inspire other centers to share their experiences with these tissues. METHODS: For every included patient and collected nerve or bone tissue specimens, we perform a detailed chart review and a multifaceted analysis of pain and pain perception immediately before surgery. We collect patient-reported outcome measures (PROMs) on pain, function, and mental well-being outcomes at preoperative assessment and at the 6-month follow-up postoperatively. Before surgery, the patient is assessed once again to obtain an immediate preoperative pain status and identify potential differences in pain intensity of different neuromas. Intraoperatively, specimens are obtained and their gross anatomical features are recorded, after which they are stored in paraformaldehyde or frozen for later sample analyses. Postoperatively, patients are contacted to obtain additional postoperative PROMs. RESULTS: A total of 220 specimens of nerve tissue have been successfully obtained from 83 limbs, comprising 95 specimens of neuromas and 125 specimens of nerves located proximal to the neuromas or from controls. CONCLUSIONS: Our approach outlines the methods combining specimen collection and examination, including both macroscopic and molecular biological features, with PROMs, encompassing physical and psychological aspects, along with clinical metadata obtained through clinical teams and chart review.

Strategies for Treating Traumatic Neuromas with Tissue-Engineered Materials.

Neuroma, a pathological response to peripheral nerve injury, refers to the abnormal growth of nerve tissue characterized by disorganized axonal proliferation. Commonly occurring after nerve injuries, surgeries, or amputations, this condition leads to the formation of painful nodular structures. Traditional treatment options include surgical excision and pharmacological management, aiming to alleviate symptoms. However, these approaches often offer temporary relief without addressing the underlying regenerative challenges, necessitating the exploration of advanced strategies such as tissue-engineered materials for more comprehensive and effective solutions. In this study, we discussed the etiology, molecular mechanisms, and histological morphology of traumatic neuromas after peripheral nerve injury. Subsequently, we summarized and analyzed current nonsurgical and surgical treatment options, along with their advantages and disadvantages. Additionally, we emphasized recent advancements in treating traumatic neuromas with tissue-engineered material strategies. By integrating biomaterials, growth factors, cell-based approaches, and electrical stimulation, tissue engineering offers a comprehensive solution surpassing mere symptomatic relief, striving for the structural and functional restoration of damaged nerves. In conclusion, the utilization of tissue-engineered materials has the potential to significantly reduce the risk of neuroma recurrence after surgical treatment.

Raman difference spectroscopy and U-Net convolutional neural network for molecular analysis of cutaneous neurofibroma.

In Neurofibromatosis type 1 (NF1), peripheral nerve sheaths tumors are common, with cutaneous neurofibromas resulting in significant aesthetic, painful and functional problems requiring surgical removal. To date, determination of adequate surgical resection margins-complete tumor removal while attempting to preserve viable tissue-remains largely subjective. Thus, residual tumor extension beyond surgical margins or recurrence of the disease may frequently be observed. Here, we introduce Shifted-Excitation Raman Spectroscopy in combination with deep neural networks for the future perspective of objective, real-time diagnosis, and guided surgical ablation. The obtained results are validated through established histological methods. In this study, we evaluated the discrimination between cutaneous neurofibroma (n = 9) and adjacent physiological tissues (n = 25) in 34 surgical pathological specimens ex vivo at a total of 82 distinct measurement loci. Based on a convolutional neural network (U-Net), the mean raw Raman spectra (n = 8,200) were processed and refined, and afterwards the spectral peaks were assigned to their respective molecular origin. Principal component and linear discriminant analysis was used to discriminate cutaneous neurofibromas from physiological tissues with a sensitivity of 100%, specificity of 97.3%, and overall classification accuracy of 97.6%. The results enable the presented optical, non-invasive technique in combination with artificial intelligence as a promising candidate to ameliorate both, diagnosis and treatment of patients affected by cutaneous neurofibroma and NF1.

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.

Mesenchymal Stem Cell Engagement Modulates Neuroma Microenviroment in Rats and Humans and Prevents Postamputation Pain.

Postamputation pain is currently managed unsatisfactorily with neuron-targeted pharmacological and interventional therapies. Non-neuronal pain mechanisms have emerged as crucial factors in the development and persistence of postamputation pain. Consequently, these mechanisms offer exciting prospects as innovative therapeutic targets. We examined the hypothesis that engaging mesenchymal stem cells (MSCs) would foster local neuroimmune interactions, leading to a potential reduction in postamputation pain. We utilized an ex vivo neuroma model from a phantom limb pain patient to uncover that the oligodeoxynucleotide IMT504 engaged human primary MSCs to promote an anti-inflammatory microenvironment. Reverse translation experiments recapitulated these effects. Thus, in an in vivo rat model, IMT504 exhibited strong efficacy in preventing autotomy (self-mutilation) behaviors. This effect was linked to a substantial accumulation of MSCs in the neuroma and associated dorsal root ganglia and the establishment of an anti-inflammatory phenotype in these compartments. Centrally, this intervention reduced glial reactivity in the dorsal horn spinal cord, demonstrating diminished nociceptive activity. Accordingly, the exogenous systemic administration of MSCs phenocopied the behavioral effects of IMT504. Our findings underscore the mechanistic relevance of MSCs and the translational therapeutic potential of IMT504 to engage non-neuronal cells for the prevention of postamputation pain. PERSPECTIVE: The present study suggests that IMT504-dependent recruitment of endogenous MSCs within severely injured nerves may prevent post-amputation pain by modifying the inflammatory scenario at relevant sites in the pain pathway. Reinforcing data in rat and human tissues supports the potential therapeutic value of IMT504 in patients suffering postamputation pain.