Targeted muscle reinnervation at the time of amputation to prevent the development of neuropathic pain.

INTRODUCTION: Targeted muscle reinnervation (TMR) is an established modality for the surgical management of neuropathic pain. Although the preventive effect of primary (acute) TMR at the time of amputation has been demonstrated previously, it remains unclear how many and which patients benefit most. Therefore, this study investigated the proportion of patients achieving sustained pain prophylaxis following amputation, as well as factors associated with its efficacy. METHODS: Primary patients who underwent TMR with a minimum follow-up of 6 months between 2018 and 2023 were enrolled. Pain outcomes (numeric rating scale [NRS], 0-10), comorbidities, and surgical factors were collected from chart review. Patients achieving sustained pain prophylaxis (NRS of ≤3 for ≥3 months until final follow-up) were identified. Multilevel mixed-effect models and multivariable regression were used to visualize pain courses and identify associated factors. RESULTS: Seventy-five patients who underwent primary TMR were included (median follow-up: 2.0 years), of whom 57.3% achieved sustained pain prophylaxis whereas 26.7% reported pain disappearance. Distal amputation levels (p = 0.036), a lower Elixhauser Comorbidity Index (p = 0.001), and the absence of psychiatric comorbidities (p = 0.039) were associated with pain prophylaxis. CONCLUSION: This study demonstrates that more than half of all patients undergoing primary TMR achieved sustained pain prophylaxis, and approximately a quarter of patients achieved sustained pain disappearance. Several factors associated with these favorable outcomes are described. These results will aid in preoperative counseling, managing patient expectations, and selecting patients who may benefit most from primary TMR surgery. LEVEL OF EVIDENCE: IV - Therapeutic.

Social Deprivation is Associated with Increased Pain in Patients Presenting with Neuropathic Pain.

Background: Neuropathic pain following nerve injury can be debilitating and negatively impact quality of life. Targeted muscle reinnervation (TMR) is an efficacious technique for the management of neuropathic pain. However, this technique may be unequally available for many geographical locations. Therefore, the aim of this study was to evaluate the association between Area Deprivation Index (ADI) and preoperative pain in patients undergoing TMR for treatment of neuropathic pain. Methods: Patients who underwent TMR for neuropathic pain in the lower and upper extremities were prospectively enrolled at our tertiary care clinic. A chart review was conducted to obtain socioeconomic, surgery, and comorbidity parameters. Preoperative pain scores (0-10 pain score index), and the ADI, reflecting deprivation status on a 0-100 scale, were collected. Results: A total of 162 patients from 13 different states were included, of which 119 were amputees (74%). The median ADI was 25 (IQR: 16-41) and the median preoperative pain score was 6 (IQR: 5-8). A higher ADI was independently associated with higher preoperative pain. The time interval from nerve injury to TMR was not associated with ADI. Conclusions: Patients undergoing surgical treatment of neuropathic pain from more socially deprived settings have increased pain experience upon initial evaluation, despite having similar time from nerve injury or amputation to TMR. These findings highlight the importance of identifying patients presenting from socially deprived settings, as this may impact their physical and mental health along with their coping mechanisms, resulting in increased pain.

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: 82 articles reported on 393 neuromas (93.2% iatrogenic) most frequently involving the lingual (44.3%), cervical plexus (14.9%), great auricular (8.5%), inferior/superior alveolar (8.3%), and occipital (7.2%) nerves. Trunk: 47 articles reported on 554 neuromas (92.9% iatrogenic) most commonly involving the intercostal (35.4%), genitofemoral (14.3%), and pudendal (12.9%) nerves. Upper extremity: 159 articles reported on 2079 neuromas (53.3% after amputation) most frequently involving the digital (46.9%), 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: 15 articles reported on 53 neuromas (100% iatrogenic) most frequently involving the biliary tract (73.9%) and vagus nerve (14.9%). 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.

Predictive Value of Preoperative Pain Sketches in Lower Extremity Amputees Undergoing Secondary Targeted Muscle Reinnervation for Treatment of Neuropathic Pain.

BACKGROUND: Targeted Muscle Reinnervation (TMR) is an effective surgical treatment for neuropathic pain in amputees. Qualitative descriptions of pain, depicted by pain sketches, could enhance the understanding of symptomatic improvement following surgery. Our aim is to assess whether pre-operative pain sketches, drawn by lower extremity (LE) amputees, can predict surgical outcomes following Secondary TMR surgery. STUDY DESIGN: Eligible patients were LE amputees who underwent Secondary TMR surgery between 2017 and 2023. Pain sketches and pain scores were prospectively collected both before and after surgery. The pain trajectory, as categorized by pre-operative pain sketches, was analyzed and assessed for improvement, defined as reaching the Minimal Clinically Important Difference (MCID). The transition into different pain sketches and the occurrence of phantom drawings were evaluated for their association with improvement. RESULTS: Fifty-eight patients were included, of which 18 (31.1%) depicted diffuse pain (DP), 26 (44.8%) depicted focal pain (FP), and 18 (24.1%) depicted radiating pain (RP) in their pre-operative sketch. FP sketches were associated with the lowest pre- and post-operative pain scores and most frequently developed into sketches indicating "no pain". RP sketches were associated with the least pain improvement, the lowest likelihood of achieving the MCID, and were more prevalent in patients with diabetes or depression. RP sketches were associated with phantom drawings; no other sketch types developed into RP sketches at the final follow-up. CONCLUSIONS: In LE amputees who underwent Secondary TMR, pre-operative pain sketches could serve as a helpful tool in predicting pain outcomes. RP sketches seemed to be associated with worse outcomes, and FP sketches with the most improvement.

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.

Fibrin Glue Coating Limits Scar Tissue Formation around Peripheral Nerves.

Scar tissue formation presents a significant barrier to peripheral nerve recovery in clinical practice. While different experimental methods have been described, there is no clinically available gold standard for its prevention. This study aims to determine the potential of fibrin glue (FG) to limit scarring around peripheral nerves. Thirty rats were divided into three groups: glutaraldehyde-induced sciatic nerve injury treated with FG (GA + FG), sciatic nerve injury with no treatment (GA), and no sciatic nerve injury (Sham). Neural regeneration was assessed with weekly measurements of the visual static sciatic index as a parameter for sciatic nerve function across a 12-week period. After 12 weeks, qualitative and quantitative histological analysis of scar tissue formation was performed. Furthermore, histomorphometric analysis and wet muscle weight analysis were performed after the postoperative observation period. The GA + FG group showed a faster functional recovery (6 versus 9 weeks) compared to the GA group. The FG-treated group showed significantly lower perineural scar tissue formation and significantly higher fiber density, myelin thickness, axon thickness, and myelinated fiber thickness than the GA group. A significantly higher wet muscle weight ratio of the tibialis anterior muscle was found in the GA + FG group compared to the GA group. Our results suggest that applying FG to injured nerves is a promising scar tissue prevention strategy associated with improved regeneration both at the microscopic and at the functional level. Our results can serve as a platform for innovation in the field of perineural regeneration with immense clinical potential.

Three Useful Tips and Tricks for Intraoperative Nerve Stimulation.

Disposable handheld nerve stimulators are widely used in peripheral nerve surgery. Such devices stimulate a motor nerve or the motor component of a mixed nerve by applying electrical current to the proximal region, targeting the main nerve trunk. This stimulation then travels along the motor nerve, reaching the distal end to control the corresponding muscle(s). In this study, the authors demonstrate three useful tips and tricks for handheld nerve stimulation during targeted muscle reinnervation and peripheral nerve surgery. The three tips are (1) identification of proximal muscle contraction by retrograde electrical stimulation of a distal sensory nerve; (2) graded stimulation for identifying motor nerves within fibrotic scarred tissue beds or parallel to the major motor/mixed nerve of interest; and (3) proximal stimulation for validation of adequate post-targeted muscle reinnervation coaptation(s).

Heterotopic Ossification Is Associated with Painful Neuromas in Transtibial Amputees Undergoing Surgical Treatment of Symptomatic Neuromas.

BACKGROUND: A relationship between nerve and osseous regeneration has been described. During the surgical treatment of symptomatic neuroma in transtibial amputees, we have noticed that heterotopic ossification (HO) depicted on preoperative radiographs appears to be associated with the location of symptomatic neuromas in both the peroneal and tibial nerve distributions. METHODS: Data were collected for transtibial amputees who underwent surgical management of symptomatic neuroma and were prospectively enrolled from 2018 through 2023. Preoperative radiographs were assessed for the presence of HO located at the distal fibula and tibia. The presence of a peroneal and/or tibial neuroma was based on findings contained within the operative reports. Pain levels were measured on a numeric rating scale (0-10). RESULTS: Sixty-five limbs of 62 amputees were include. Peroneal neuroma and presence of fibular HO (P=0.001), and tibial neuroma and presence of tibial HO (P=0.038) demonstrated an association. The odds of having a symptomatic peroneal neuroma with fibular HO present are greater than the odds of a symptomatic peroneal neuroma when fibular HO is absent (OR 9.3; 95%CI [1.9-45.6], P=0.006). Pre-operative pain scores were significantly higher for all patients with HO (P<0.001), those with fibular HO (P<0.001), and those with tibial HO (P<0.001), compared to patients without HO. CONCLUSIONS: In patients with symptomatic neuromas, preoperative pain was worse when HO was present in the transtibial amputee's residual limb. Further research on the neuroma-HO-complex in symptomatic amputees is required. LEVEL OF EVIDENCE: Therapeutic Level IV.

Biology and pathophysiology of symptomatic neuromas.

ABSTRACT: Neuromas are a substantial cause of morbidity and reduction in quality of life. This is not only caused by a disruption in motor and sensory function from the underlying nerve injury but also by the debilitating effects of neuropathic pain resulting from symptomatic neuromas. A wide range of surgical and therapeutic modalities have been introduced to mitigate this pain. Nevertheless, no single treatment option has been successful in completely resolving the associated constellation of symptoms. While certain novel surgical techniques have shown promising results in reducing neuroma-derived and phantom limb pain, their effectiveness and the exact mechanism behind their pain-relieving capacities have not yet been defined. Furthermore, surgery has inherent risks, may not be suitable for many patients, and may yet still fail to relieve pain. Therefore, there remains a great clinical need for additional therapeutic modalities to further improve treatment for patients with devastating injuries that lead to symptomatic neuromas. However, the molecular mechanisms and genetic contributions behind the regulatory programs that drive neuroma formation-as well as the resulting neuropathic pain-remain incompletely understood. Here, we review the histopathological features of symptomatic neuromas, our current understanding of the mechanisms that favor neuroma formation, and the putative contributory signals and regulatory programs that facilitate somatic pain, including neurotrophic factors, neuroinflammatory peptides, cytokines, along with transient receptor potential, and ionotropic channels that suggest possible approaches and innovations to identify novel clinical therapeutics.

The Peripheral Nerve Surgeon's Role in the Management of Neuropathic Pain.

Neuropathic pain (NP) underlies significant morbidity and disability worldwide. Although pharmacologic and functional therapies attempt to address this issue, they remain incompletely effective for many patients. Peripheral nerve surgeons have a range of techniques for intervening on NP. The aim of this review is to enable practitioners to identify patients with NP who might benefit from surgical intervention. The workup for NP includes patient history and specific physical examination maneuvers, as well as imaging and diagnostic nerve blocks. Once diagnosed, there is a range of options surgeons can utilize based on specific causes of NP. These techniques include nerve decompression, nerve reconstruction, nerve ablative techniques, and implantable nerve-modulating devices. In addition, there is an emerging role for preoperative involvement of peripheral nerve surgeons for cases known to carry a high risk of inducing postoperative NP. Lastly, we describe the ongoing work that will enable surgeons to expand their armamentarium to better serve patients with NP.

"Pain Sketches Demonstrate Patterns of Pain Distribution and Pain Progression following Primary Targeted Muscle Reinnervation in Amputees."

BACKGROUND: Numerical scales are validated methods to report pain outcomes after Targeted Muscle Reinnervation (TMR) but do not include the assessment of qualitative pain components. This study evaluates the application of pain sketches within a cohort of patients undergoing primary TMR and describes differences in pain progression according to early postoperative sketches. METHODS: This study included 30 patients with major limb amputation and primary TMR. Patients' drawings were categorized into four categories of pain distribution (focal (FP), radiating (RP), diffuse (DP) and no pain (NP)) and inter-rater reliability was calculated. Secondly, pain outcomes were analyzed for each category. Pain scores were the primary and Patient-Reported Outcomes Measurement Information System (PROMIS) instruments were the secondary outcomes. RESULTS: The inter-rater reliability for the sketch categories was good (overall Kappa coefficient of 0.8). The NP category reported a mean decrease in pain of 4.8 points, followed by the DP (2.5 points) and FP categories (2.0 points). The RP category reported a mean increase in pain of 0.5 points. For PROMIS Pain Interference and Pain Intensity, the DP category reported a mean decrease of 7.2 and 6.5 points respectively, followed by the FP category (5.3 and 3.6 points). The RP category reported a mean increase of 2.0 points in PROMIS Pain Interference and a mean decrease of 1.4 points in PROMIS Pain Intensity. Secondary outcomes for the NP category were not reported. CONCLUSIONS: Pain sketches demonstrated reliability in pain morphology assessment and might be an adjunctive tool for pain interpretation in this setting.