Evaluation of RPNI for Symptomatic Neuromas in Lower Limb Amputees

Official title

The Effect of Regenerative Peripheral Nerve Interface (RPNI) Surgery on Neuropathic Pain and Functional Outcomes in Major Lower Extremity Amputations

Overview

This prospective, observational cohort study evaluates the long-term outcomes of Regenerative Peripheral Nerve Interface (RPNI) surgery in patients with major lower extremity amputations suffering from symptomatic neuromas. RPNI is a surgical technique where the transected nerve end is implanted into a free autologous muscle graft to serve as a physiological target for reinnervation. The study aims to objectively assess the reduction in mechanical hypersensitivity using Pressure Pain Threshold (PPT) measurements via a digital algometer. Additionally, it monitors subjective neuropathic pain levels, functional mobility, and prosthesis satisfaction over a 24-month follow-up period compared to pre-operative baselines.

Detailed description

Scientific Rationale and Background Traditional "passive" nerve management techniques (e.g., traction neurectomy, burying in muscle/bone) often fail to prevent neuroma recurrence due to the lack of a physiological target for regenerating axons. This study investigates the long-term efficacy of the "Regenerative Peripheral Nerve Interface (RPNI)" technique. RPNI is an "active" surgical approach where the transected nerve end is implanted into a free autologous muscle graft to promote physiological reinnervation, thereby preventing chaotic axonal sprouting and neuroma formation.

Diagnostic Protocol (The Clinical Triad) To ensure accurate participant selection and strictly exclude non-neuroma pathologies such as Complex Regional Pain Syndrome (CRPS), the study employs a standardized "Clinical Triad" protocol for all potential candidates:

1. Neuropathic Validation: Confirmation of neuropathic pain character via validated questionnaires. 2. Anatomical Localization: Identification of a specific trigger point with a positive Tinel's sign triggering radiating paresthesia. 3. Radiological Confirmation: Visualization of the neuroma bulb at the symptomatic site using high-resolution Diagnostic Ultrasound.

Surgical Methodology (Standard of Care) Participants undergo the standard RPNI procedure as per the clinic's routine protocol.

* Graft Harvesting: A free autologous muscle graft (approx. 30x15x5 mm) is harvested. To minimize donor site morbidity, graft selection is standardized based on the amputation level: Vastus Lateralis for transtibial amputees and Biceps Femoris for transfemoral amputees. * Inlay Technique: The neuroma bulb is excised, and the fresh nerve end is implanted into the center of the muscle graft using the "Inlay Technique" to maximize neurotization interface and minimize axonal escape.

Investigational Modules

* Viscero-Somatic Convergence: The study uniquely investigates the potential "cross-talk" mechanism between pelvic autonomic nerves (parasympathetic S2-S4) and somatic nerves. Participants are monitored for "Viscero-Somatic Symptoms," defined as stump pain triggered specifically by micturition, defecation, or sexual activity. * Phantom Motor Execution (PME): As a functional indicator of reinnervation, patients are assessed for the ability to voluntarily execute movements with their phantom limb.

Sample Size and Power Analysis Based on a priori power analysis using G\*Power 3.1 software, the sample size was calculated referencing the pressure pain threshold (PPT) effect sizes reported in comparable literature (Kubiak et al., 2022). Assuming a large effect size (Cohen's d = 1.5), an alpha error of 0.05, and a power of 90% (1-beta), a minimum of 13 participants is required to detect statistical significance. To account for a potential 20% dropout rate over the 24-month follow-up, the target enrollment is set at 20 patients.

Statistical Analysis Plan Data analysis will be performed using IBM SPSS Statistics 26.0.

* Normality Testing: The Shapiro-Wilk test will be used to determine the distribution of continuous variables. * Longitudinal Analysis: The Friedman Test will be employed to analyze changes in dependent variables (NRS, DN4, PPT, PEQ scores) across the five time points (Pre-op, 3, 6, 12, 24 months). * Pairwise Comparisons: Significant differences identified by the Friedman test will be further analyzed using the Wilcoxon Signed-Rank Test with Bonferroni correction. * Correlation: Spearman's correlation analysis will be used to assess the relationship between objective algometer measurements and subjective prosthesis usage time (DPUT). * Significance Level: A p-value of \<0.05 will be considered statistically significant.

Interventions

• Procedure Regenerative Peripheral Nerve Interface (RPNI) Surgery
  The surgical procedure is standardized as follows to preserve the residual limb (stump) anatomy: * Approach: An 8-10 cm incision is made on the lateral thigh. For transtibial (below-knee) amputees, the incision is placed approximately 15 cm proximal to the knee joint. For transfemoral (above-knee) amputees, it is placed 5-10 cm proximal to the distal end of the residual limb. * Nerve Dissection: The sciatic nerve is isolated, dissected, and transected at its most distal point. Subsequently, it

Primary outcome measures

• Change in Pressure Pain Threshold (PPT) [Time frame: Baseline (Pre-op), 3, 6, 12, and 24 months post-operation.]

Secondary outcome measures (8)

• Change in Pain Intensity (NRS) [Time frame: Baseline, 3, 6, 12, and 24 months.]
• Change in Neuropathic Pain Characteristics (DN4 Score) [Time frame: Baseline, 3, 6, 12, and 24 months.]
• Prosthesis Satisfaction and Quality of Life (PEQ) [Time frame: Baseline, 3, 6, 12, and 24 months.]
• Change in Functional Mobility (TUG Test) [Time frame: Baseline, 3, 6, 12, and 24 months.]
• Daily Prosthesis Usage Time (DPUT) [Time frame: Baseline, 3, 6, 12, and 24 months.]
• Quality of Phantom Motor Execution (PME) [Time frame: Baseline (Pre-op), 3, 6, 12, and 24 months post-operation.]
• Severity of Viscero-Somatic Convergence Symptoms [Time frame: Baseline (Pre-op), 3, 6, 12, and 24 months post-operation.]
• Incidence of New Heterotopic Ossification (HO) [Time frame: Baseline (Pre-op) and 24 months post-operation.]

Eligibility criteria

Inclusion criteria

• Age: Adults aged 18 to 70 years.
• Amputation Status: Unilateral major lower extremity amputation (Transtibial, Transfemoral, or Knee Disarticulation).
• Radiological Baseline: Absence of Heterotopic Ossification (HO) in the residual limb, confirmed by pre-operative X-rays (Walter Reed Classification Grade 0).
• Diagnosis: Confirmed diagnosis of "Symptomatic Neuroma" validated by the Clinical Triad:

• Neuropathic Pain: DN4 Questionnaire score ≥ 4.
• Pain Intensity: Numeric Rating Scale (NRS) score ≥ 4.
• Physical Exam: Positive Tinel's sign or palpation tenderness at a specific trigger point.
• Radiology: Diagnostic Ultrasound visualization of the neuroma bulb.
• Surgical Indication: Scheduled for RPNI surgery as part of the routine standard of care treatment protocol due to prosthesis intolerance or severe pain.
• Consent: Willing and able to provide informed consent and attend follow-up visits.

Exclusion criteria

• CRPS: Diagnosis of Complex Regional Pain Syndrome (CRPS Type 1 or 2).
• Concurrent Bone Surgery: Patients requiring simultaneous stump revision surgery (e.g., bone shortening, osteotomy, spur excision) or having existing HO (Walter Reed Grade > 0).
• Systemic Conditions: Uncontrolled diabetes mellitus (HbA1c > 8.5%) or severe peripheral arterial disease compromising wound healing.
• Cognitive Status: Cognitive impairment or psychiatric conditions preventing reliable completion of patient-reported outcome measures (PEQ, DN4).
• History: Previous RPNI surgery at the same site (Recurrent RPNI cases).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Turkey (Türkiye) · 1 center

• University of Health Sciences, Gulhane Training and Research Hospital, Department of Ortho — Ankara

Publications

• Yuan M, Gallo M, Gallo L, Huynh MH, McRae M, McRae MC, Thoma A, Coroneos CJ, Voineskos SH. Targeted Muscle Reinnervation and Regenerative Peripheral Nerve Interfaces Versus Standard Management in the Treatment of Limb Amputation: A Systematic Review and Meta-Analysis. Plast Surg (Oakv). 2024 May;32(2):253-264. doi: 10.1177/22925503221107462. Epub 2022 Jun 16. PMID 38681253
• Watson CPN, Midha R, Ng DW. Causalgia: A Review of Nerve Resection, Amputation, Immunotherapy, and Amputated Limb CRPS II Pathology. Can J Neurol Sci. 2024 May;51(3):351-356. doi: 10.1017/cjn.2023.260. Epub 2023 Jul 25. PMID 37489506
• Vaskov A, Wallace D, Desai K, Laidlaw A, Kung T, Gates D, Kemp S, Chestek C, Cederna P. A Robust Neuromuscular Interface to Restore Lost Function in People with Amputations. Res Sq [Preprint]. 2025 May 14:rs.3.rs-5989030. doi: 10.21203/rs.3.rs-5989030/v1. PMID 40470247
• Senger JL, Thorkelsson A, Wang BY, Chan KM, Kemp SWP, Webber CA. Comparison of 2 Regenerative Peripheral Nerve Interface Techniques for the Treatment of Rat Neuroma Pain. Plast Reconstr Surg. 2024 Aug 1;154(2):346-349. doi: 10.1097/PRS.0000000000010911. Epub 2023 Jul 4. PMID 37400949
• Raasveld FV, Lehle CH, Hwang CD, Cross RE, Husseini JS, Simeone FJ, Newman ET, Tuano K, Lozano-Calderon SA, Valerio IL, Eberlin KR. The influence of nerve surgical techniques at time of amputation on the prevalence of heterotopic ossification in transtibial amputees. Injury. 2025 Feb;56(2):112047. doi: 10.1016/j.injury.2024.112047. Epub 2024 Nov 20. PMID 39608134
• Pettersen E, Sassu P, Pedrini FA, Granberg H, Reinholdt C, Breyer JM, Roche A, Hart A, Ladak A, Power HA, Leung M, Lo M, Valerio I, Eberlin KR, Ko J, Dumanian GA, Kung TA, Cederna P, Ortiz-Catalan M. Regenerative Peripheral Nerve Interface: Surgical Protocol for a Randomized Controlled Trial in Postamputation Pain. J Vis Exp. 2024 Mar 15;(205). doi: 10.3791/66378. PMID 38557950
• Lin Z, Yu P, Chen Z, Li G. Regenerative peripheral nerve interface reduces the incidence of neuroma in the lower limbs after amputation: a retrospective study based on ultrasound. J Orthop Surg Res. 2023 Aug 24;18(1):619. doi: 10.1186/s13018-023-04116-6. PMID 37620955
• Lans J, Groot OQ, Hazewinkel MHJ, Kaiser PB, Lozano-Calderon SA, Heng M, Valerio IL, Eberlin KR. Factors Related to Neuropathic Pain following Lower Extremity Amputation. Plast Reconstr Surg. 2022 Aug 1;150(2):446-455. doi: 10.1097/PRS.0000000000009334. Epub 2022 Jul 27. PMID 35687412

Identifiers

NCT: NCT07420192 · RPNI-SBU-AMPUTEE-2026 · 2026-24

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗