Beyond Limb Salvage: Limb Restoration Efforts Following Remote Combat-Related Extremity Injuries Optimize Outcomes and Support Sustained Surgical Readiness.

Where Are We Now? Surgeons have changed how they manage patients with malignant tumors of the extremities over the last four decades, with the largest transition being the switch to limb salvage rather than amputation for the large majority of patients with bone sarcomas [8, 10, 12]. Indeed, modern day decision-making generally favors limb salvage in the absence of a specific contraindication [8]. Still, because some patients will undergo amputations, surgeons continue to try to improve how we perform these procedures. Areas of focus include amputation techniques as well as methods of preventing phantom limb pain and neuromas; generally, these studies focus on patient-reported outcomes and healthcare-related quality of life [3, 13]. Some of the more exciting discoveries have been on the topic of preventing nerve-related pain using targeted muscle reinnervation (TMR) [6], regenerative peripheral nerve interfaces (RPNI) [5], as well as other neuroma revision and prevention concepts. The current study by Döring et al. [2] is important because it focuses on the long-term outcomes and complications from the subset of patients who may not be good candidates for limb salvage. Where Do We Need To Go? Nerve-associated pain and associated sequelae can lead to poor functional outcomes and decreased mobility and prosthetic use. Research focused on minimizing these complications is an essential next step to improving function and quality of life for patients with sarcoma and limb loss. Although TMR was originally conceived of to allow autonomous zones for myoelectric prosthesis use in the upper extremity, the added benefit of decreased phantom limb pain and neuroma formation has made it an appealing technique for the lower extremity as well. A concern for TMR is that a specialized team is usually required to complete the procedure and it can increase OR time [5, 6]. RPNI has also shown excellent potential for prevention of these same nerve-related sequelae [5], and it is technically simpler and potentially easier for a wider range of surgeons. While TMR seems to have the best outcomes, it may not be a reality for widespread clinical use (due to the need for specialized teams to perform the procedure). In contrast, RPNI may be more practical because it can be performed by a non-hand surgery–trained surgeon. Well-designed studies looking at the two techniques prospectively are still needed. We also need to determine the impact each technique has on long-term pain and amputee function. Döring et al. [2] provide long-term functional and quality-of-life data for patients with amputation, which can serve as a baseline for future studies focused on amputation techniques. A large proportion of amputation-related studies focus on populations with the highest rates of amputation. This includes older patients with diabetes- or peripheral vascular disease–related complications [3, 13] as well as military and traumatic amputations [4, 11]. While these data are valuable, younger patients with sarcoma are quite different than those patient populations. Therefore, future research should focus on this younger patient group since those who survive their tumors would be expected to have both long life expectancy and high functional demands [9]. How Do We Get There? Due to the rarity of amputation for sarcoma in a younger population, a well-designed multicenter study comparing TMR and RPNI techniques would be a valuable collaborative effort. One study [1], which was the largest oncologic cohort to date (31 patients from a single institution treated with TMR for oncologic amputation), found that on short-term follow-up (1 year), the study group compared favorably to the control group, whose data were collected from a national amputee database. Building off of this study, researchers should compare TMR versus RPNI in a prospective study and include patient-reported as well as functional outcomes with a focus on prosthesis use [7]. Patient-reported outcomes and prosthesis use can be compared at 1, 3, and 5 years to definitively compare the techniques. Modern day prosthetic fitting and technology use should be integrated into this study, as well as a detailed cost analysis that examines the differences in resource requirements for the two techniques.

Targeted muscle reinnervation and regenerative peripheral nerve interfaces for pain prophylaxis and treatment: A systematic review.

Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) procedures have been shown to improve patient-reported outcomes for the treatment of symptomatic neuromas after amputation; however, the specific indications and comparative outcomes of each are unclear. The primary research questions were what complement of nerves most frequently requires secondary pain intervention after conventional amputation, whether this information can guide the focused application of TMR and RPNI to the primary amputation setting, and how the outcomes compare in both settings. We performed a retrospective review of records for patients who had undergone lower-extremity TMR and/or RPNI at our institution. Eighty-seven procedures were performed: 59 for the secondary treatment of symptomatic neuroma pain after amputation and 28 for primary prophylaxis during amputation. We reviewed records for the amputation level, TMR and/or RPNI timing, pain scores, patient-reported resolution of nerve-related symptoms, and complications or revisions. We evaluated the relationship between the amputation level and the frequency with which each transected nerve required neurologic intervention for pain symptoms. The mean pain score decreased after delayed TMR or RPNI procedures from 4.3 points to 1.7 points (p < 0.001), and the mean final pain score (and standard deviation) was 1.0 ± 1.9 points at the time of follow-up for acute procedures. Symptom resolution was achieved in 92% of patients. The sciatic nerve most commonly required intervention for symptomatic neuroma above the knee, and the tibial nerve and common or superficial peroneal nerve were most problematic following transtibial amputation. None of our patients required a revision pain treatment procedure after primary TMR targeting these commonly symptomatic nerves. Failure to address the tibial nerve during a delayed procedure was associated with an increased risk of unsuccessful TMR, resulting in a revision surgical procedure (odds ratio, 26 [95% confidence interval, 1.8 to 368]; p = 0.02). There is a consistent pattern of symptomatic nerves that require secondary surgical intervention for the management of pain after amputation. TMR and RPNI were translated to the primary amputation setting by using this predictable pattern to devise a surgical strategy that prevents symptomatic neuroma pain. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) can reduce neuroma formation and phantom limb pain (PLP) after lower extremity (LE) amputation. These techniques have not been studied in safety-net hospitals. This study aims to examine the surgical complication rates after TMR and/or RPNI at an academic safety-net hospital in an urban setting. This was a retrospective review of patients older than 18 years who had prior above-knee guillotine amputation (AKA) or below-knee guillotine amputation (BKA) and underwent stump formalization with TMR and/or RPNI from 2020 to 2022. Demographics, medical history, and operative and postoperative characteristics were collected. The primary outcome was any surgical complication, defined as infection, dehiscence, hematoma, neuroma, or reoperation. Univariate analysis was conducted to identify variables associated with surgical complications and PLP. Thirty-two patients met the inclusion criteria. The median age was 52 years, and 75% were males. Indications for amputation included diabetic foot infection (71.9%), necrotizing soft tissue infection (25.0%), and malignancy (3.1%). BKA was the most common indication for formalization (93.8%). Most patients (56.3%) had formalization with TMR and RPNI, 34.4% patients had TMR only, and 9.4% had RPNI alone. The incidence of postoperative complications was 46.9%, with infection being the most common (31.3%). The median follow-up time was 107.5 days. There was no significant difference in demographics, medical history, or operative characteristics between patients who did and did not have surgical complications. However, there was a trend toward higher rates of PLP in patients who had a postoperative wound infection (p = 0.06). Overall complication rates after LE formalization with TMR and/or RPNI at our academic safety-net hospital were consistent with reported literature. Given the benefits, including reduced chronic pain and lower health care costs, we advocate for the wider adoption of these techniques at other safety-net hospitals.

The agonist-antagonist myoneural interface (AMI) technique at the time of transtibial amputation involves the use of agonist-antagonist muscle pairs to restore natural contraction-stretch relationships and to improve proprioceptive feedback when utilizing a prosthetic limb1. Utilizing the standard incision for a long posterior myofasciocutaneous flap, the lateral and medial aspects of the limb are dissected, identifying and preserving the superficial peroneal and saphenous nerve, respectively. The tendons of the tibialis anterior and peroneus longus are transected distally to allow adequate length for the AMI constructs. After ligation of the anterior tibial vessels, the deep peroneal nerve is identified and tagged to create a regenerative peripheral nerve interface (RPNI). The tibia and fibula are cut approximately 15 cm from the medial joint line, facilitating dissection of the deep posterior compartment and ligation of the peroneal and posterior tibial vessels. The tendons of the lateral gastrocnemius and tibialis posterior are transected distally, and the amputation is completed. The extensor retinaculum is harvested from the residual limb along with multiple 2 × 3-cm free muscle grafts, which will be used for the RPNI constructs. The retinaculum is secured to the tibia with suture anchors, and AMI pairs of the lateral gastrocnemius and tibialis anterior as well as the tibialis posterior and peroneus longus are constructed. Separate RPNIs of the major lower-extremity nerves are performed, and the wound is closed in a standard layered fashion. An isometric myodesis of the gastrocnemius without coaptation of agonist-antagonist muscle pairs can be performed at the time of transtibial amputation. The AMI technique restores natural agonist-antagonist relationships at the time of transtibial amputation to increase proprioceptive feedback and improve prosthetic control. These outcomes contrast with those of a traditional isometric myodesis, which prevents proprioceptive communication from the residual limb musculature to the central nervous system. Additionally, the AMI technique allows for concentric and eccentric muscular contractions, which may contribute to the maintenance of limb volume and aid with prosthetic fitting, as opposed to the typical limb atrophy observed following standard transtibial amputation1,2. With the development and availability of more advanced prostheses, the AMI technique offers more precise control and increases the functionality of these innovative devices. Early clinical outcomes of the AMI technique at the time of transtibial amputation have been promising. In a case series of the first 3 patients who underwent the procedure, complications were minor and consisted of 2 episodes of cellulitis and 1 case of delayed wound healing1. Muscle activation measured through electromyography demonstrated an improved ability to limit unintended muscular co-contraction with attempted movement of the phantom limb, as compared with patients who underwent a standard transtibial amputation1. Additionally, residual limb volume was maintained postoperatively without the need for substantial prosthetic modifications. The tendons of the tibialis anterior, peroneus longus, tibialis posterior, and lateral gastrocnemius should be transected as distal as possible to allow adequate length for creation of the AMI constructs.Approximately 2 × 3-cm free muscle grafts are harvested from the amputated extremity for RPNI3.Smooth tendon-gliding through the synovial tunnels should be confirmed before closure. If necessary, muscle debulking can improve gliding and decrease the size of the residual limb.Harvesting the extensor retinaculum for synovial tunnels has been our preferred method, although we acknowledge that other grafts options such as the tarsal tunnel are available1. RPNI = regenerative peripheral nerve interfaceAMI = agonist-antagonist myoneural interfaceEMG = electromyographic.

Outcomes of targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) in the oncologic population are limited. We sought to examine the safety and effectiveness of TMR and RPNI in controlling postamputation pain in the oncologic population. A retrospective cohort study of consecutive patients who underwent oncologic amputation followed by immediate TMR or RPNI was conducted from November 2018 to May 2022. The primary study outcome was postamputation pain, assessed using the Numeric Pain Scale and Patient-Reported Outcomes Measurement Information System (PROMIS) for residual limb pain (RLP) and phantom limb pain (PLP). Secondary outcomes included postoperative complications, tumor recurrence, and opioid use. Sixty-three patients were evaluated for a mean follow-up period of 11.3 months. The majority of patients (65.1%) had a history of previous limb salvage. At final follow-up, patients had an average Numeric Pain Scale score for RLP of 1.3 ± 2.2 and for PLP, 1.9 ± 2.6. The final average raw PROMIS measures were pain intensity 6.2 ± 2.9 (T-score 43.5), pain interference 14.6 ± 8.3 (T-score 55.0), and pain behavior 39.0 ± 22.1 (T-score 53.4). Patient opioid use decreased from 85.7% preoperatively to 37.7% postoperatively and morphine milligram equivalents decreased from a mean of 52.4 ± 53.0 preoperatively to 20.2 ± 38.4 postoperatively. In the oncologic population TMR and RPNI are safe surgical techniques associated with significant reductions in RLP, PLP, and improvements in patient-reported outcomes. This study provides evidence for the routine incorporation of TMR and RPNI in the multidisciplinary care of oncologic amputees.

Postamputation pain is a spectrum of debilitating sensations that impacts millions of people in the United States. While the development of postamputation pain, including phantom limb pain (PLP), is multifactorial, it has been associated with disorganized axonal sprouting, resulting in a neuroma and subsequent central nervous system changes. Nerve reconstruction surgeries, such as regenerative peripheral nerve interface (RPNI) and targeted muscle reinnervation (TMR), provide transected nerve fibers with proper target organs for reinnervationand have been shown to significantly reduce PLP. This case series aims to describe perioperative peripheral nerve blocks as a diagnostic tool for identifying patients who would benefit from RPNI or TMR. We conducted a retrospective search of patients who underwent major extremity amputation and who received a diagnostic peripheral nerve block before undergoing reconstructive nerve surgery (TMR and/or RPNI). Six patients (58-80 years old) with below-knee amputations (BKA) were examined. All patients experienced a reduction in postamputation pain (PAP), specifically PLP, after a diagnostic peripheral nerve block (PNB). The average time between amputation and revision surgery was approximately two years (Mean: 22.35 months). Following surgical intervention, all patientsreported a reduction in PLP episodes after nerve reconstruction surgery. Two patients no longer reported PLP.Ambulation rates also improved following revision (50% vs 83%). PNBs can be used as an effective diagnostic tool to identify patients that will significantly benefit from amputation revisions with TMR or RPNI.

This study investigated the relative cost utility of three techniques for the management of symptomatic neuromas after neuroma excision: (1) implantation of nerve into muscle, (2) targeted muscle reinnervation (TMR), and (3) regenerative peripheral nerve interface (RPNI). The costs associated with each procedure were determined using Common Procedural Terminology codes in combination with data from the Centers for Medicaid and Medicare Services Physician and Facility 2020 Fee Schedules. The relative utility of the three procedures investigated was determined using changes in Patient-Reported Outcomes Measurement Information System (PROMIS) and Numeric Rating Scale (NRS) pain scores as reported per procedure. The relative utility of each procedure was reported in terms of quality-adjusted life years (QALYs), as is standard in the literature. The least expensive option for the surgical treatment of painful neuromas was nerve implantation into an adjacent muscle. In contrast, for the treatment of four neuromas, as is common postamputation, TMR without a microscope was found to cost $50,061.55 per QALY gained, TMR with a microscope was found to cost $51,996.80 per QALY gained, and RPNI was found to cost $14,069.28 per QALY gained. While RPNI was more expensive than nerve implantation into muscle, it was still below the standard willingness-to-pay threshold of $50,000 per QALY, while TMR was not. Evaluation of costs and utilities associated with the various surgical options for the management of painful neuromas suggest that nerve implantation into muscle is the least expensive option with the best improvement in QALY, while demonstrating comparable outcomes to TMR and RPNI with regard to pain symptoms.

PURPOSE: The outcomes of targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) in oncologic amputees have been limited to small series. Herein, we report the MD Anderson experience with the surgical and postamputation outcomes of TMR and RPNI in the oncologic population. METHODS: We conducted a retrospective cohort study of consecutive patients who underwent oncologic amputation followed by TMR or RPNI from November 2018 to May 2022. Patient-reported Outcomes Measurement System (PROMIS) and Numerical Rating Scales for residual limb pain (RLP) and phantom limb pain (PLP) were obtained and compared with published benchmarked outcomes. RESULTS: We compared 68 patients with oncologic amputation at our institution with 727 patients with benchedmarked outcomes. Patients had mean follow-up period of 10.9±8.7 months. Oncologic amputees experienced significant reductions in pain intensity (-5.39; 95%CI,-4.28, -6.50; p<0.001), interference (-11.98; 95%CI, -8.19, -15.8; p<0.001), behavior (-32.95; 95%CI, -25.5,-40.4; p<0.001) and global health (-26.25; 95%CI, -22.09, -30.42; p<0.001) following TMR or RPNI from baseline to final follow-up. Delayed wound healing was the most common complication (14.7%) and tumor recurrence occurred in 36.8% of patients. Compared with benchedmarked outcomes, oncologic amputees who underwent TMR or RPNI demonstrated significantly lower median PLP (0.0 vs. 4.0, p<0.001), RLP (1.0 vs. 4, p<0.001), pain intensity (6.0 vs. 46.6, p<0.001), pain interference (9.5 vs. 55.9, p<0.001), and pain behavior (36.0 vs. 56.7, p<0.001) scores. CONCLUSION: Oncologic amputees who underwent TMR and RPNI demonstrated significant reductions in postamputation pain compared with their baseline and benchedmarked outcomes with relatively low postoperative complications rate.

Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) prevent symptomatic neuroma formation in amputees. Forearm-level amputations present multiple muscular targets, making it challenging to determine the ideal treatment. The purpose of this study was to evaluate the best TMR targets, role of RPNI, and appropriate patient-selection criteria in forearm-level amputations. We hypothesized that deep and distal TMR targets would best prevent symptomatic neuromas, RPNI would prove a success adjunct, and patients with poorly controlled diabetes would not develop symptomatic neuromas regardless of nerve management. We retrospectively identified forearm-level amputations performed between 2017 and 2022. Patients with TMR by outside providers, follow-up <6 months, or insufficient documentation were excluded. Demographics, surgical nerve management, and postoperative complications were collected. The primary outcome was development of a painful neuroma determined by the Eberlin criteria. Patients undergoing TMR were divided a priori into two groups, superficial and proximal versus deep and distal TMR targets, and were compared. Thirty-nine patients met inclusion criteria, and 16 developed a symptomatic neuroma. No patients with a deep or distal TMR target developed a symptomatic neuroma. One nerve out of 12 treated with RPNI developed a symptomatic neuroma. No patient with poorly controlled diabetes developed a symptomatic neuroma, despite no advanced nerve management. In a case series of forearm amputations, deep and distal TMR targets prevented symptomatic neuroma formation more than superficial and proximal targets. Regenerative peripheral nerve interface is a useful adjunct for neuroma control, especially for the radial sensory nerve. Patients with poorly controlled diabetes may not require advanced nerve management. Level IV retrospective case series.

Utilization of Techniques for Upper Extremity Amputation Neuroma Treatment and Prevention

Upper limb loss results in significant physical and psychological impairment and is a major financial burden for both patients and healthcare services. Current myoelectric prostheses rely on electromyographic (EMG) signals captured using surface electrodes placed directly over antagonistic muscles in the residual stump to drive a single degree of freedom in the prosthetic limb (e.g., hand open and close). In the absence of the appropriate muscle groups, patients rely on activation of biceps/triceps muscles alone (together with a mode switch) to control all degrees of freedom of the prosthesis. This is a non-physiological method of control since it is non-intuitive and contributes poorly to daily function. This leads to the high rate of prosthetic abandonment. Targeted muscle reinnervation (TMR) reroutes the ends of nerves in the amputation stump to nerves innervating “spare” muscles in the amputation stump or chest wall. These then become proxies for the missing muscles in the amputated limb. TMR has revolutionised prosthetic control, especially for high-level amputees (e.g., after shoulder disarticulation), resulting in more intuitive, fluid control of the prosthesis. TMR can also reduce the intensity of symptoms such as neuroma and phantom limb pain. Regenerative peripheral nerve interface (RPNI) is another technique for increasing the number of control signals without the limitations of finding suitable target muscles imposed by TMR. This involves wrapping a block of muscle around the free nerve ending, providing the regenerating axons with a target organ for reinnervation. These RPNIs act as signal amplifiers of the previously severed nerves and their EMG signals can be used to control prosthetic limbs. RPNI can also reduce neuroma and phantom limb pain. In this review article, we discuss the surgical technique of TMR and RPNI and present outcomes from our experience with TMR.

PROCESS guided case series of primary targeted muscle reinnervation and regenerative peripheral nerve interfaces in the prevention of post amputation and phantom limb pain.

Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) surgeries manage neuroma pain; however, there remains considerable discord regarding the best treatment strategy. We provide a direct comparison of TMR and RPNI surgery using a rodent model for the treatment of neuroma pain. The tibial nerve of 36 Fischer rats was transected and secured to the dermis to promote neuroma formation. Pain was assessed using mechanical stimulation at the neuroma site (direct pain) and von Frey analysis at the footpad (to assess tactile allodynia from collateral innervation). Once painful neuromas were detected 6 weeks later, animals were randomized to experimental groups: (a) TMR to the motor branch to biceps femoris, (b) RPNI with an extensor digitorum longus graft, (c) neuroma excision, and (d) neuroma in situ. The TMR/RPNIs were harvested to confirm muscle reinnervation, and the sensory ganglia and nerves were harvested to assess markers of regeneration, pain, and inflammation. Ten weeks post-TMR/RPNI surgery, animals had decreased pain scores compared with controls ( P < .001) and they both demonstrated neuromuscular junction reinnervation. Compared with neuroma controls, immunohistochemistry showed that sensory neuronal cell bodies of TMR and RPNI showed a decrease in regeneration markers phosphorylated cyclic AMP receptor binding protein and activation transcription factor 3 and pain markers transient receptor potential vanilloid 1 and neuropeptide Y ( P < .05). The nerve and dorsal root ganglion maintained elevated Iba-1 expression in all cohorts. RPNI and TMR improved pain scores after neuroma resection suggesting both may be clinically feasible techniques for improving outcomes for patients with nerve injuries or those undergoing amputation.

From concept to clinical practice-Unraveling the adoption of regenerative peripheral nerve interface (RPNI) surgery.