"Decreasing Postamputation Pain with the Regenerative Peripheral Nerve Interface (RPNI)".

Over 185,000 limb amputations are performed in the United States annually, many of which are due to the sequelae of peripheral vascular disease. Symptomatic neuromas remain a significant source of postamputation morbidity and contribute to both phantom limb (PLP) and residual limb pain (RLP). While many interventions have been proposed for the treatment of symptomatic neuromas, conventional methods lead to a high incidence of neuroma recurrence. Furthermore, these existing methods do not facilitate an ability to properly interface with myoelectric prosthetic devices. The Regenerative Peripheral Nerve Interface (RPNI) was developed to overcome these limitations. The RPNI consists of an autologous free muscle graft secured around the end of a transected nerve. The muscle graft provides regenerating axons with end organs to reinnervate, thereby preventing neuroma formation. We have shown that this simple, reproducible, and safe surgical technique successfully treats and prevents neuroma formation in major limb amputations. In this paper, we describe RPNI surgery in the setting of major limb amputation and highlight the promising results of RPNIs in our animal and clinical studies.

An ultrasonographic and electromyographic evaluation of jumping stump possibly due to a neuroma in a patient with transradial amputation: A case report.

BACKGROUND AND OBJECTIVE: Jumping stump is an uncommon movement disorder characterized by involuntary movements and severe neuropathic pain in the stump. The pathophysiology and etiology of this phenomenon have not yet been clearly elucidated, and unfortunately, no proven treatment with successful recovery exists. This report aims to describe a severe painful jumping stump, possibly due to neuromas, in a traumatic transradial amputee. MATERIALS AND METHOD: We performed ultrasound examination of the painful stump depicted neuroma. Electromyographic evaluation of the stump revealed arrhythmic motor unit action potentials (MUAPs) with normal duration and amplitude; other movement disorders, such as myokymia and fasciculations, were excluded. Ultrasound should be preferred to magnetic resonance imaging (MRI) for evaluation of stumps in patients with painful stump because MRI may not be helpful due to motion artefacts. The involuntary movements ceased after surgical excision of the neuroma following failure of conservative treatments. CONCLUSION: This report confirms that neuromas are clearly associated with jumping stump. Ultrasonographic and electromyographic assessments are necessary to reveal the features of this pathology for treatment planning.

Targeted Muscle Reinnervation Improves Residual Limb Pain, Phantom Limb Pain, and Limb Function: A Prospective Study of 33 Major Limb Amputees.

BACKGROUND: Targeted muscle reinnervation is an emerging surgical technique to treat neuroma pain whereby sensory and mixed motor nerves are transferred to nearby redundant motor nerve branches. In a recent randomized controlled trial, targeted muscle reinnervation was recently shown to reduce postamputation pain relative to conventional neuroma excision and muscle burying. QUESTIONS/PURPOSES: (1) Does targeted muscle reinnervation improve residual limb pain and phantom limb pain in the period before surgery to 1 year after surgery? (2) Does targeted muscle reinnervation improve Patient-reported Outcome Measurement System (PROMIS) pain intensity and pain interference scores at 1 year after surgery? (3) After 1 year, does targeted muscle reinnervation improve functional outcome scores (Orthotics Prosthetics User Survey [OPUS] with Rasch conversion and Neuro-Quality of Life [Neuro-QOL])? METHODS: Data on patients who were ineligible for randomization or declined to be randomized and underwent targeted muscle reinnervation for pain were gathered for the present analysis. Data were collected prospectively from 2013 to 2017. Forty-three patients were enrolled in the study, 10 of whom lacked 1-year follow-up, leaving 33 patients for analysis. The primary outcomes measured were the difference in residual limb and phantom limb pain before and 1 year after surgery, assessed by an 11-point numerical rating scale (NRS). Secondary outcomes were change in PROMIS pain measures and change in limb function, assessed by the OPUS Rasch for upper limbs and Neuro-QOL for lower limbs before and 1 year after surgery. RESULTS: By 1 year after targeted muscle reinnervation, NRS scores for residual limb pain from 6.4 ± 2.6 to 3.6 ± 2.2 (mean difference -2.7 [95% CI -4.2 to -1.3]; p < 0.001) and phantom limb pain decreased from 6.0 ± 3.1 to 3.6 ± 2.9 (mean difference -2.4 [95% CI -3.8 to -0.9]; p < 0.001). PROMIS pain intensity and pain interference scores improved with respect to residual limb and phantom limb pain (residual limb pain intensity: 53.4 ± 9.7 to 44.4 ± 7.9, mean difference -9.0 [95% CI -14.0 to -4.0]; residual limb pain interference: 60.4 ± 9.3 to 51.7 ± 8.2, mean difference -8.7 [95% CI -13.1 to -4.4]; phantom limb pain intensity: 49.3 ± 10.4 to 43.2 ± 9.3, mean difference -6.1 [95% CI -11.3 to -0.9]; phantom limb pain interference: 57.7 ± 10.4 to 50.8 ± 9.8, mean difference -6.9 [95% CI -12.1 to -1.7]; p ≤ 0.012 for all comparisons). On functional assessment, OPUS Rasch scores improved from 53.7 ± 3.4 to 56.4 ± 3.7 (mean difference +2.7 [95% CI 2.3 to 3.2]; p < 0.001) and Neuro-QOL scores improved from 32.9 ± 1.5 to 35.2 ± 1.6 (mean difference +2.3 [95% CI 1.8 to 2.9]; p < 0.001). CONCLUSIONS: Targeted muscle reinnervation demonstrates improvement in residual limb and phantom limb pain parameters in major limb amputees. It should be considered as a first-line surgical treatment option for chronic amputation-related pain in patients with major limb amputations. Additional investigation into the effect on function and quality of life should be performed. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Regenerative Peripheral Nerve Interfaces for Prevention and Management of Neuromas.

Symptomatic neuromas are a common cause of postamputation pain that can lead to significant disability. Regenerative peripheral nerve interface surgery is performed to treat symptomatic neuromas and prevent the development of neuromas. This review delineates the clinical problem of postamputation pain, describes the limitations of the available treatment methods, and highlights the need for an effective treatment strategy that leverages the biologic processes of nerve regeneration and muscle reinnervation. The evidence supporting use of regenerative peripheral nerve interface surgery to mitigate neuroma formation is discussed and the rationale behind the efficacy of regenerative peripheral nerve interfaces is explored.

Neuromas and postamputation pain.

Postamputation stump and phantom pain are highly prevalent but remain a difficult condition to treat. The underlying mechanisms are not fully clarified, but growing evidence suggests that changes in afferent nerves, including the formation of neuromas, play an important role. The main objective of this cross-sectional study was to investigate whether ultrasound-verified neuroma swellings are more frequent in amputees with postamputation pain than in amputees without pain (primary outcome). Sixty-seven amputees were included. Baseline characteristics including the frequency and intensity of spontaneous stump and phantom pain were obtained, and sensory characteristics and evoked responses were assessed. A high-frequency ultrasound examination of the amputated extremity was performed to obtain information on the presence, size, and elasticity of swollen neuromas and pressure pain thresholds. Swollen neuromas were present in 53 (79.1%) of the 67 amputees included in the study, in 47 (82.5%) of 57 amputees with pain and in 6 (60.0%) of 10 amputees without pain (P = 0.2). No difference was found in stump pain intensity (P = 0.42) during the last week or in phantom pain intensity in the last month (P = 0.74) between amputees with and without swollen neuromas. Our findings suggest that it is not the presence of swollen neuromas itself that drives postamputation pain. However, changes in the transected nerve endings may still be crucial for driving postamputation pain because a positive Tinel sign was significantly more frequent in amputees with pain, irrespectively of the degree of neuroma swelling.

Neuroma of the Infrapatellar branch of the saphenous nerve following Total knee Arthroplasty: a case report.

BACKGROUND: Injury to the infrapatellar branch of the saphenous nerve (IBSN) is common during total knee arthroplasty (TKA) with a standard midline skin incision. Occasionally, painful neuromas form at the transection of nerve and cause pain and limitation of the range of motion of the knee joint. CASE PRESENTATION: A 70-year-old woman experienced right knee pain and stiffness for 4 years after TKA. Physical assessment revealed medial tenderness; Tinel's sign was positive. Radiographs revealed that the prosthesis was well-placed and well-fixed. She was diagnosed with arthrofibrosis and possible neuroma after TKA. She underwent right knee exploration, neurectomy, adhesiolysis and spacer exchange. The neuroma-like tissue was sent for pathological examination. The patient recovered uneventfully and at 3-month follow-up reported no recurrence of pain or stiffness. The pathological report confirmed the diagnosis of neuroma. CONCLUSIONS: IBSN injury should be a concern if surgeons encounter a patient who has pain and stiffness after TKA. Tinel's sign, local anesthetic injection, MRI and ultrasound could help the diagnosis and identify the precise location of neuroma. Surgical intervention should be performed if necessary.

Painful Traumatic Neuromas in Subcutaneous Fat: Visibility and Morphologic Features With Ultrasound.

OBJECTIVES: Subcutaneous neuromas usually result from trauma and may lead to dissatisfaction in patients with a trigger point, loss of sensitivity in the relevant territory of innervation, and spontaneous neuropathic pain. Confirming clinically suspected cases of neuroma may prove difficult. The objective of this study was to evaluate the visibility and morphologic features of traumatic subcutaneous neuromas of the limbs with ultrasound (US). METHODS: Between January 2012 and August 2016, 38 consecutive patients clinically suspected of having subcutaneous neuromas were investigated with US. The diagnosis was confirmed on the basis of a focal morphologic abnormality of the nerve associated with trigger pain. Each neuroma was classified into 1 of 3 subtypes based on its injury pattern. The subtypes were terminal neuroma, spindle neuroma, and scar encasement, either isolated or associated with these subtypes. RESULTS: Forty-four lesions were found in the 38 patients, including 29 spindle neuromas (65.9%), 14 terminal neuromas (31.8%) and 1 scar encasement with no nerve caliber abnormality (2.3%). Fifteen neuromas (35% of all neuromas) were associated with scar encasement. In 13 cases that required surgery, the diagnosis of neuroma or scar encasement could be surgically proven and confirmed the validity of the US findings. CONCLUSIONS: Ultrasound can be used to show and classify subcutaneous nerves of the upper and lower limbs with high accuracy. The US trigger sign provides an indication of neuroma involvement in pain. This modality can play a substantial role both in the preoperative planning of neuroma surgery and in therapeutic US-guided procedures.

Time course of traumatic neuroma development.

This study was designed to characterize morphologic stages during neuroma development post amputation with an eye toward developing better treatment strategies that intervene before neuromas are fully formed. Right forelimbs of 30 Sprague Dawley rats were amputated and limb stumps were collected at 3, 7, 28, 60 and 90 Days Post Amputation (DPA). Morphology of newly formed nerves and neuromas were assessed via general histology and neurofilament protein antibody staining. Analysis revealed six morphological characteristics during nerve and neuroma development; 1) normal nerve, 2) degenerating axons, 3) axonal sprouts, 4) unorganized bundles of axons, 5) unorganized axon growth into muscles, and 6) unorganized axon growth into fibrotic tissue (neuroma). At early stages (3 & 7 DPA) after amputation, normal nerves could be identified throughout the limb stump and small areas of axonal sprouts were present near the site of injury. Signs of degenerating axons were evident from 7 to 90 DPA. From day 28 on, variability of nerve characteristics with signs of unorganized axon growth into muscle and fibrotic tissue and neuroma formation became visible in multiple areas of stump tissue. These pathological features became more evident on days 60 and 90. At 90 DPA frank neuroma formation was present in all stump tissue. By following nerve regrowth and neuroma formation after amputation we were able to identify 6 separate histological stages of nerve regrowth and neuroma development. Axonal regrowth was observed as early as 3 DPA and signs of unorganized axonal growth and neuroma formation were evident by 28 DPA. Based on these observations we speculate that neuroma treatment and or prevention strategies might be more successful if targeted at the initial stages of development and not after 28 DPA.

Painful Neuroma Treatment of the Supraorbital Nerve and Forehead Neurotization Using Human Cadaveric Nerve Allograft.

Neuroma pain can be severe, persistent, and treatment-resistant. Forehead and scalp anesthesia is troublesome for patients. Following an iatrogenic ablative injury to the right supraorbital nerve, with subsequent painful neuroma formation, a human cadaveric nerve allograft (AxoGen, Alachua, FL) was used to restore sensation of the right forehead and treat pain. At 1-year follow-up, the patient was pain-free, and protective sensation to the right forehead was recovered with comparable static and dynamic 2-point discrimination between the injured (20 mm, 12 mm respectively) and the normal side (15 mm, 10 mm respectively). This is the first reported case of using a cadaver nerve allograft for successful direct neurotization of the skin and restoration of sensation in the upper part of the face, and for treating painful neuromas. Moreover, a brief review of the available techniques for treating neuromas of the supraorbital and supratrochlear nerves is provided.

Swimming Training Reduces Neuroma Pain by Regulating Neurotrophins.

INTRODUCTION: Neuroma formation after peripheral nerve transection leads to severe neuropathic pain in amputees. Previous studies suggested that physical exercise could bring beneficial effect on alleviating neuropathic pain. However, the effect of exercise on neuroma pain still remained unclear. In addition, long-term exercise can affect the expression of neurotrophins (NT), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), which play key roles in nociceptor sensitization and nerve sprouting after nerve injury. Here, we investigated whether long-term swimming exercise could relieve neuroma pain by modulating NT expression. METHODS: We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. After TNT surgery, rats performed swimming exercise for 5 wk. Neuroma pain and tactile sensitivities were detected using von Frey filaments. Immunofluorescence was applied to analyze neuroma formation. NGF and BDNF expressions in peripheral neuroma, dorsal root ganglion, and the spinal cord were measured using enzyme-linked immunosorbent assay and Western blotting. RESULTS: TNT led to neuroma formation, induced neuroma pain, and mechanical allodynia in hind paw. Five-week swimming exercise inhibited neuroma formation and relieved mechanical allodynia in the hind paw and neuroma pain in the lateral ankle. The analgesic effect lasted for at least 1 wk, even when the exercise ceased. TNT elevated the expressions of BDNF and NGF in peripheral neuroma, dorsal root ganglion, and the spinal cord to different extents. Swimming also decreased the elevation of NT expression. CONCLUSIONS: Swimming exercise not only inhibits neuroma formation induced by nerve transection but also relieves pain behavior. These effects might be associated with the modulation of NT.

Comparison of Different Sequences of Magnetic Resonance Imaging and Ultrasonography with Nerve Conduction Studies in Peripheral Neuropathies.

BACKGROUND: Peripheral neuropathies refer to a group of disorders in which there is damage to the nerves of the peripheral nervous system. Electrophysiologic studies are the main stay for the diagnosis of peripheral neuropathies. However, direct visualization of the nerves is possible with exact localization of site of disease with high-resolution ultrasonography (USG) and 3-Tesla magnetic resonance imaging (MRI) scanner, and newer magnetic resonance (MR) sequences. METHODS: We performed a cross-sectional study including 55 patients and 64 nerves with upper limb peripheral neuropathies. All patients included underwent high-resolution focused USG of the nerves and MR neurography. A nerve conduction velocity study was performed for reference. RESULTS: The diagnostic confidence of the turbo spin echo T2-weighted (T2W) MR sequence was seen to be highest, with a sensitivity of 95.31%, whereas it was 81.25% for USG. Continuity of the nerve in patients with traumatic neuropathy was seen in 65.7% and 62.86% (22/35) nerves on MRI and USG, respectively. T1-weighted and T2W MR sequences were seen to be equally effective in establishing the continuity of the nerve. Increase in the caliber/thickening was seen in 77% of cases on MRI and 73.8% of cases on USG. Neuroma formation was seen equally on both MR and USG in 60.66%. We consistently found low fractional anisotropy (FA) values at the site of disease. CONCLUSIONS: USG is a sensitive technique to diagnose peripheral neuropathies and it should be used as a screening modality for focused MR to be performed later. Turbo spin echo T2W fast spin has the highest sensitivity to identify nerve disease and is comparable with nerve conduction studies. Among the newer sequences, diffusion tensor imaging should be performed to increase diagnostic confidence.

Multiple Neuromas Cause Painful "Jumping Stump" in a Transfemoral Amputee: A Case Report.

Painful "jumping stump" is an uncommon but very disturbing complication postamputation. This condition is one of the movement disorder entities resulting from peripheral nerve pathology, often known as "peripherally induced movement disorders." Previously case reports have been written about painful and nonpainful incidence of "jumping stump"; however, only the earliest "jumping stump" article in 1852 suspected that neuromas might influence the involuntary movement. In this study, we describe a 38-year-old man with bilateral transfemoral amputee who suffered from painful "jumping stump" with multiple neuromas confirmed by imaging. He was treated successfully by ultrasound-guided phenol injection into the sciatic neuroma stalks. The pathophysiology of jumping stump and its possible association with neuroma are briefly discussed.

Spontaneous activity in C-fibres after partial damage to the saphenous nerve in mice: Effects of retigabine.

BACKGROUND: Spontaneous pain is the most devastating positive symptom in neuropathic pain patients. Recent data show a direct relationship between spontaneous discharges in C-fibres and spontaneous pain in neuropathic patients. Unfortunately, to date there is a lack of experimental animal models for drug testing. METHODS: We recorded afferent fibres from a new experimental model in vitro. The preparation contains a neuroma formed in a peripheral branch of the saphenous nerve together with the undamaged branches, which maintain intact terminals in a skin flap. RESULTS: Fibres with stable rates of ectopic spontaneous discharges were found among axotomized (5 A- and 18 C-fibres, mean discharge 0.48 ± 0.08 Hz) and 'putative intact' fibres (12 C-fibres, mean discharge 0.28 ± 0.08 Hz). A proportion (~9%) of axotomized fibres had mechanical receptive fields in the skin far beyond the site of injury. Collision experiments demonstrated that action potentials evoked from neuroma and skin travelled by the same fibre, indicating functional cross-talk between neuromatose and putative intact fibres. Retigabine, the specific Kv7 channel opener, depressed spontaneous discharges by 70% in 15/18 units tested. In contrast, responses to mechanical stimulation of the skin were unaltered by retigabine. CONCLUSIONS: Partial damage to a peripheral nerve may increase the incidence of spontaneous activity in C-fibres. Retigabine reduced spontaneous activity but not stimulus-evoked activity, suggesting an important role for ion channels in the control of spontaneous pain and demonstrating the utility of the model for the testing of compounds in clinically relevant variables. WHAT DOES THIS STUDY ADD?: Our in vitro experimental model of peripheral neuropathy allows for pharmacological characterization of spontaneously active fibres. Using this model, we show that retigabine inhibits aberrant spontaneous discharges without altering physiological responses in primary afferents.

Anthropogenic Radio-Frequency Electromagnetic Fields Elicit Neuropathic Pain in an Amputation Model.

Anecdotal and clinical reports have suggested that radio-frequency electromagnetic fields (RF EMFs) may serve as a trigger for neuropathic pain. However, these reports have been widely disregarded, as the epidemiological effects of electromagnetic fields have not been systematically proven, and are highly controversial. Here, we demonstrate that anthropogenic RF EMFs elicit post-neurotomy pain in a tibial neuroma transposition model. Behavioral assays indicate a persistent and significant pain response to RF EMFs when compared to SHAM surgery groups. Laser thermometry revealed a transient skin temperature increase during stimulation. Furthermore, immunofluorescence revealed an increased expression of temperature sensitive cation channels (TRPV4) in the neuroma bulb, suggesting that RF EMF-induced pain may be due to cytokine-mediated channel dysregulation and hypersensitization, leading to thermal allodynia. Additional behavioral assays were performed using an infrared heating lamp in place of the RF stimulus. While thermally-induced pain responses were observed, the response frequency and progression did not recapitulate the RF EMF effects. In vitro calcium imaging experiments demonstrated that our RF EMF stimulus is sufficient to directly contribute to the depolarization of dissociated sensory neurons. Furthermore, the perfusion of inflammatory cytokine TNF-α resulted in a significantly higher percentage of active sensory neurons during RF EMF stimulation. These results substantiate patient reports of RF EMF-pain, in the case of peripheral nerve injury, while confirming the public and scientific consensus that anthropogenic RF EMFs engender no adverse sensory effects in the general population.

Post-traumatic neuroma due to closed nerve injury. Is recovery after peripheral nerve trauma related to ultrasonographic neuroma size?

OBJECTIVE: traumatic neuroma is a pathological condition of peripheral nervous system consisting of localized proliferation of injured nerve elements. The symptoms depend on the type of involved nerve (motor and/or sensitive) and on the site and the extension of the lesion. Ultrasound is the best tool to depict the morphology of nerve, especially in traumatic conditions. We present a study aimed to assess the correlation between the degree of nerve function and the ultrasound morphology of neuromas. PATIENTS AND METHODS: we retrospectively evaluated 18 patients with neuromas (not transected) occurred after a closed nerve trauma evaluated with clinical and ultrasound assessment. The clinical evaluation was related to the % of increase of cross sectional area as detected by nerve ultrasound respect to normal nerve. RESULTS: we observed that dimensions of neuromas are not related to function until neuroma have cross sectional area 5 times enlarged respect to normal nerve, in this case recovery never occurs. CONCLUSION: our study failed to clear detect a relation between cross sectional area enlargement of neuroma and nerve function, but showed a cut off beyond which prognosis is negative. This result provide some useful information for prognosis, nevertheless we believe that future perspective studies are needed to better understand the timing of developing neuromas and its evolution.

The recurrent Morton neuroma: what now?

Interdigital neuromas are a common cause of forefoot pain, and approximately 80% of patients require surgical excision for symptom relief. Although 50% to 85% of patients obtain relief after primary excision, symptoms may recur because of an incorrect diagnosis, inadequate resection, or adherence of pressure on a nerve stump neuroma. The symptom relief rate after reoperation is similar to that after primary excision. A plantar longitudinal incision provides optimal exposure, and transposition of the nerve stump into bone or muscle and avoids traction or pressure on the nerve ending that can result in a painful stump neuroma. Preoperative counseling is essential to align patient expectations with potential outcomes.

Effect of local application of an antibody against brain-derived neurotrophic factor on neuroma formation after transection of the inferior alveolar nerve in the rat.

This study aimed to examine the contributions of brain-derived neurotrophic factor (BDNF) at the injury site toward neuroma formation and nerve regeneration after inferior alveolar nerve transection. Histological analysis confirmed neuroma formation at 2 weeks after complete transection of the inferior alveolar nerve. A local administration of an antibody to BDNF inhibited connective tissue proliferation at the injury site and promoted nerve fiber integrity. Fluorogold labeling showed a significantly higher number of labeled cells in the trigeminal ganglion in the anti-BDNF-treated group compared with the vehicle control group. In-situ hybridization histochemistry showed intense signals for tropomyosin receptor kinase B mRNA in the area of the injury site containing fibrous or granular tissue in the anti-BDNF-treated group. In contrast, these signals were close to the detection limit in the area of the perineurium in intact nerve trunks, indicating that the signals were expressed by fibroblasts within the connective tissue. These findings suggest that antagonization of endogenous BDNF induced by nerve injury reduces neuroma formation, without inhibiting damaged axon regeneration.

Simple electrodiagnostic method for Morton neuroma.

INTRODUCTION: We describe a simple and quickly applied electrodiagnostic method for confirming the diagnosis of interdigital neuropathy caused by Morton neuroma (MN). METHODS: Interdigital nerves II-III and III-IV were stimulated with surface electrodes simultaneously touching the lateral side of 1 toe and the medial side of the other. Recording was also made with surface electrodes. The results of 20 normal controls and 14 patients with MN were evaluated. RESULTS: The amplitude and peak latency values elicited in the patients as well as the interside differences revealed an acceptable abnormality rate between 57.1% and 71.4%. CONCLUSIONS: Although the most popular and effective method of MN diagnosis is clinical evaluation supported by imaging, electrophysiological studies can, in selected patients, provide valuable information.