Lower Extremity Amputations, Neuropathic Pain, Phantom Limb Pain After Amputation, Residual Limb Pain, Symptomatic Neuroma
Conditions
Keywords
RPNI, Regenerative Peripheral Nerve Interface, Pressure Pain Threshold, PPT, Algometry, Prosthesis Satisfaction, Viscero-Somatic Convergence, Phantom Motor Execution
Brief summary
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
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 is separated into the Common Peroneal and Tibial divisions. * Fascicular Separation: Based on nerve thickness, intraneural dissection is performed to split the Common Peroneal nerve into 1 or 2 fascicles, and the Tibial nerve into 2 to 4 fascicles. * Graft Harvesting: Autologous muscle grafts are harvested to wrap these created fascicles. The donor site is standardized by amputation level: Vastus Lateralis muscle for transtibial amputees and Biceps Femoris muscle for transfemoral amputees.
Sponsors
Saglik Bilimleri Universitesi
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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: 1. Neuropathic Pain: DN4 Questionnaire score ≥ 4. 2. Pain Intensity: Numeric Rating Scale (NRS) score ≥ 4. 3. Physical Exam: Positive Tinel's sign or palpation tenderness at a specific trigger point. 4. 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pressure Pain Threshold (PPT) | Baseline (Pre-op), 3, 6, 12, and 24 months post-operation. | Objective measurement of mechanical hypersensitivity at the neuroma site using a digital pressure algometer. The device applies increasing pressure in kg/cm² until the patient reports pain. Measurements are taken from the most tender point of the neuroma and a control point. Higher values indicate higher pain tolerance (improvement). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pain Intensity (NRS) | Baseline, 3, 6, 12, and 24 months. | Self-reported pain intensity measured by the Numeric Rating Scale (NRS). Scale ranges from 0 (No pain) to 10 (Worst possible pain). |
| Change in Neuropathic Pain Characteristics (DN4 Score) | Baseline, 3, 6, 12, and 24 months. | Assessment using the Douleur Neuropathique 4 (DN4) questionnaire. Total score ranges from 0 to 10. A score of 4 or higher indicates neuropathic pain. |
| Prosthesis Satisfaction and Quality of Life (PEQ) | Baseline, 3, 6, 12, and 24 months. | Evaluation using the Turkish validated version of the Prosthesis Evaluation Questionnaire (PEQ). Scores are normalized to a 0-100 scale (Higher scores indicate better outcome). |
| Change in Functional Mobility (TUG Test) | Baseline, 3, 6, 12, and 24 months. | Timed Up and Go (TUG) test measuring the time (in seconds) required to stand, walk 3 meters, turn, walk back, and sit down. Lower time indicates better mobility. |
| Daily Prosthesis Usage Time (DPUT) | Baseline, 3, 6, 12, and 24 months. | Self-reported average duration of prosthesis usage per day, measured in hours/day. |
| Quality of Phantom Motor Execution (PME) | Baseline (Pre-op), 3, 6, 12, and 24 months post-operation. | Assessment of the patient's ability to voluntarily execute specific movements with the phantom limb. Documenting the change from pre-operative baseline to post-operative reinnervation status. Rated on a 3-point ordinal scale: 0 (None): No contraction or movement sensation felt. 1. (Weak/General): Contraction felt, but unable to distinguish specific movement (General stump contraction). 2. (Strong/Clear): Distinct contraction specific to the intended movement (e.g., thumb vs. wrist) is felt clearly. Higher scores indicate superior motor control. |
| Severity of Viscero-Somatic Convergence Symptoms | Baseline (Pre-op), 3, 6, 12, and 24 months post-operation. | Assessment of "Viscero-Somatic Convergence" (cross-talk between pelvic autonomic nerves and somatic nerves). Participants are queried about stump or phantom pain triggered by 1) Micturition, 2) Defecation, and 3) Sexual activity. Each item is rated on a 3-point ordinal scale (0=No, 1=Mild, 2=Severe). Total score ranges from 0 to 6. The goal is to observe if RPNI surgery reduces or eliminates these pre-existing cross-talk symptoms compared to baseline. |
| Incidence of New Heterotopic Ossification (HO) | Baseline (Pre-op) and 24 months post-operation. | Radiological evaluation of new bone formation in soft tissues at the amputation stump using standard A/P and Lateral X-rays. Baseline Requirement: All participants must have a Grade 0 status at baseline to be eligible. Post-Op Grading: At 24 months, any new ossification is graded according to the Walter Reed Classification System: * Grade 0: No ectopic bone formation within the soft-tissue envelope. * Grade I (Mild): 0%-25% of the soft-tissue envelope occupied by ectopic bone. * Grade II (Moderate): \>25%-50% of the soft-tissue envelope occupied by ectopic bone. * Grade III (Severe): \>50% of the soft-tissue envelope occupied by ectopic bone. Outcomes will be reported as the frequency of each grade developed post-operatively. |
Countries
Turkey (Türkiye)
Contacts
CONTACTAhmet Burak Bilekli, MD, Associate Professor
CONTACTMuhammed Burak Polat, MD
PRINCIPAL_INVESTIGATORAhmet Burak Bilekli, MD, Associate Professor
University of Health Sciences, Gülhane Training and Research Hospital
Outcome results
None listed