Computer assisted surgical anatomy mapping (CASAM) of the distal Posterior Interosseous Nerve (PIN) and its relation to the wrist arthroscopy portals: A cadaver study.

Introduction: The distal Posterior Interosseous Nerve (PIN) plays an important part in the sensory innervation of the wrist joint. Introduction of the arthroscopy portals during wrist arthroscopy might injure the PIN. The anatomic variation in the trajectory of the PIN and the proximity to the dorsal arthroscopy portals have not yet been fully explored. Materials and methods: Computer assisted surgical anatomy mapping (CASAM) is a technique to digitally compute and merge photographic images using anatomic landmarks and visualize variation in anatomy. A standard wrist arthroscopy procedure was carried out on eight cadaver forearms. CASAM was used to map the trajectory of the distal PIN and measure the distance to bony landmarks and the nearest wrist arthroscopy portals. Descriptive statistics were provided for anatomical measurements. Results: CASAM illustrated great variation in the PIN trajectories between the specimens. The mean distance from the PIN to Lister's tubercle was 9 â€‹mm (range 3-14, SD 3.9), the distance to the ulnar styloid was 27 â€‹mm (range 23-32, SD 3.3). None of the nerves showed signs of iatrogenic injury from placement of the arthroscopy portals. The 3-4 portal and the 6R portal were closest to the PIN with a respective mean distance of 9 â€‹mm (range 4-15, SD 3.8) and 19 â€‹mm (range 13-22, SD 3.2). Conclusion: CASAM demonstrated the importance of understanding nerve anatomy variations and offered insight into which arthroscopy portals are most likely to damage the distal PIN. However, we conclude that the overall risk of PIN injury from wrist arthroscopy is low due to the proximity to the portals.

Aptis Distal Radioulnar Joint Arthroplasty: A Multicenter Evaluation of Functional Outcomes, Complications, and Patient Satisfaction.

Background The Aptis distal radioulnar joint (DRUJ) implant has been commonly used to replace the DRUJ and restore wrist function in patients with a severely destroyed DRUJ. Objective Promising results have been described in the literature. However, the clinical results in a multicenter setting are sparse and variable. This study evaluates the short- to midterm clinical results of 53 patients with a (mean) follow-up of 51 months. Patients and Methods Fifty-three patients (59 implants) treated between 2011 and 2020 in three different institutions were retrospectively identified in a prospectively collected database. The main indication for Aptis DRUJ arthroplasty was a destroyed DRUJ and gross distal radioulnar instability and isolated DRUJ osteoarthritis. Functional outcome, complications, and patient satisfaction were evaluated. Patients completed the Patient-Rated Wrist Evaluation (PRWE) questionnaire and an additional questionnaire about patient satisfaction and return to hobby/work. Results Implant survival was 92%, the surgical follow-up showed many complications (64,4%), and revision surgery was needed frequently (40.7%). In 13 cases, the follow-up was longer than 5 years. Three reimplantations had to be performed and two implants were permanently explanted. In spite of this all, wrist and forearm motion as well as pain reduction was adequate and patient satisfaction was reasonable (72.2%). Conclusion The Aptis DRUJ arthroplasty is a viable option that can provide adequate wrist and forearm function after secure patient selection and surgical placement of the implant in the wrist with a good bone stock of the radius. The complication rate was found to be high, yet patient satisfaction was reasonable. In the case of secondary surgery, additional surgery seems to be needed. For primary surgery, the implant seems to be successful without complications. Different complications have been described, but further analysis is warranted to find the causes of complications and to objectify the performance of the Aptis DRUJ implant. Level of Evidence IV.

Survival after resection of malignant peripheral nerve sheath tumors: Introducing and validating a novel type-specific prognostic model.

Background: This study aimed to assess the performance of currently available risk calculators in a cohort of patients with malignant peripheral nerve sheath tumors (MPNST) and to create an MPNST-specific prognostic model including type-specific predictors for overall survival (OS). Methods: This is a retrospective multicenter cohort study of patients with MPNST from 11 secondary or tertiary centers in The Netherlands, Italy and the United States of America. All patients diagnosed with primary MPNST who underwent macroscopically complete surgical resection from 2000 to 2019 were included in this study. A multivariable Cox proportional hazard model for OS was estimated with prespecified predictors (age, grade, size, NF-1 status, triton status, depth, tumor location, and surgical margin). Model performance was assessed for the Sarculator and PERSARC calculators by examining discrimination (C-index) and calibration (calibration plots and observed-expected statistic; O/E-statistic). Internal-external cross-validation by different regions was performed to evaluate the generalizability of the model. Results: A total of 507 patients with primary MPNSTs were included from 11 centers in 7 regions. During follow-up (median 8.7 years), 211 patients died. The C-index was 0.60 (95% CI 0.53-0.67) for both Sarculator and PERSARC. The MPNST-specific model had a pooled C-index of 0.69 (95%CI 0.65-0.73) at validation, with adequate discrimination and calibration across regions. Conclusions: The MPNST-specific MONACO model can be used to predict 3-, 5-, and 10-year OS in patients with primary MPNST who underwent macroscopically complete surgical resection. Further validation may refine the model to inform patients and physicians on prognosis and support them in shared decision-making.

VCA supercooling in a swine partial hindlimb model.

Vascularized composite allotransplantations are complex procedures with substantial functional impact on patients. Extended preservation of VCAs is of major importance in advancing this field. It would result in improved donor-recipient matching as well as the potential for ex vivo manipulation with gene and cell therapies. Moreover, it would make logistically feasible immune tolerance induction protocols through mixed chimerism. Supercooling techniques have shown promising results in multi-day liver preservation. It consists of reaching sub-zero temperatures while preventing ice formation within the graft by using various cryoprotective agents. By drastically decreasing the cell metabolism and need for oxygen and nutrients, supercooling allows extended preservation and recovery with lower ischemia-reperfusion injuries. This study is the first to demonstrate the supercooling of a large animal model of VCA. Porcine hindlimbs underwent 48 h of preservation at - 5 °C followed by recovery and normothermic machine perfusion assessment, with no issues in ice formation and favorable levels of injury markers. Our findings provide valuable preliminary results, suggesting a promising future for extended VCA preservation.

Multidisciplinary strategies to treat painful mononeuropathies in the upper extremity: from lab to bedside.

Neuropathic pain in the upper extremity is a serious problem, commonly involving relatively young patients. The pain causes loss of function and productivity, changes a patient's lifestyle and can progress into a chronic pain syndrome with secondary psychosocial co-morbidities. Treating patients with a painful mononeuropathy remains challenging, with a monodisciplinary approach often having limited treatment efficacy. This narrative review discusses how to deal with this challenge in the treatment of patients with peripheral nerve injury pain, addressing the four important pillars: (1) diagnosing a painful mononeuropathy; (2) clinical pain phenotyping; (3) personalized pain treatment; and (4) using a multidisciplinary team approach.

Patient-reported esthetic outcomes following lower extremity free flap reconstruction: A cross-sectional multicenter study.

INTRODUCTION: The goal of lower-extremity reconstructions is primarily to salvage the leg; however, esthetic outcomes are also important. This study aimed to assess the impact of a lower extremity free tissue transfer regarding social functioning, patient-reported esthetic outcomes, and possible differences between fasciocutaneous vs. muscle flaps. MATERIAL AND METHODS: For this cross-sectional multicenter study, patients operated between 2003 and 2021, with a minimum follow-up of 12 months, were identified. Outcomes were obtained from 89 patients. Patient-reported outcomes were assessed using a questionnaire containing 5-point Likert scale questions grouped in three groups: aspect of the reconstructed leg, the aspect of the donor site, and the negative impact on social functioning. Physical functioning and mental health were assessed with the Short-Form-36. RESULTS: The overall score for negative impact on social functioning was 22.2. This was 46.7 for the esthetic satisfaction of the reconstructed leg and 57.1 for the donor site. No significant differences were seen between patients who underwent a reconstruction with a fasciocutaneous flap compared to a muscle flap. Secondary surgical procedures for improving the esthetic aspect were performed in 12% of the patients in the fasciocutaneous group and 0% in the muscle group. CONCLUSION: Our results show that the most optimal esthetic outcome is not defined by the type of flap. We found a strong correlation between physical functioning and the negative impact on social functioning that a reconstructed lower extremity may have. The result of this study can be taken into consideration during the shared decision-making process of choosing the most optimal reconstruction.

Clinical Results of Nonvascularized Metatarsal Articular Bone Grafting for Osteochondral Defects of the Radiocarpal and Distal Radioulnar Joint.

Background Treatment of post-traumatic osteochondral defects in the radiocarpal and distal radioulnar joint with nonvascularized metatarsal articular bone grafting is an option to restore the joint (cartilage) surface and wrist function. Purpose To evaluate the clinical midterm results of 10 consecutive patients who were treated with a nonvascularized metatarsal bone graft for cartilage bone defects of the lunate facet, scaphoid facet, sigmoid notch, or the radial part of the ulnar head. Patients and Methods Patients with isolated osteochondral defects of the lunate facet, scaphoid facet, sigmoid notch, or radial part of the ulnar head, respectively, as a result of wrist trauma were retrospectively identified in a prospectively collected database. The patients symptoms were limited wrist motion and/or pain. Clinical results and complications were extracted from patient's medical files and two questionnaires consisting of the Patient-Rated Wrist Evaluation and additional questions regarding patient satisfaction and return to work and/or hobby. Results Minor complications occurred in three cases and required surgery. In five cases an acceptable donor site foot morbidity was seen at 1 year. One patient was not satisfied due to persistent wrist pain despite adequate range of motion. One patient could not return to its prior work. Another patient could not resume its hobby. Conclusion Retrospective evaluation of 10 cases with resurfacing of the scaphoid facet, sigmoid notch, and/or lunate facet, or radial part of the ulnar head has shown that osseointegration was possible without a vascular pedicle to the graft in all cases with a (mean) follow-up of 5 years. This technique may become an alternative treatment when implants become less available. Level of Evidence Level III.

Mental health is strongly associated with capability after lower extremity injury treated with free flap limb salvage or amputation.

BACKGROUND: Knowledge about factors associated with long-term outcomes, after severe traumatic injury to the lower extremity, can aid with the difficult decision whether to salvage or amputate the leg and improve outcome. We therefore studied factors independently associated with capability at a minimum of 1 year after amputation or free flap limb salvage. METHODS: We included 135 subjects with a free flap lower extremity reconstruction and 41 subjects with amputation, between 1991 and 2021 at two urban-level 1 trauma centers with a mean follow-up of 11 ± 7 years. Long-term physical functioning was assessed using the Physical Component Score (PCS) of the Short-Form 36 (SF36) and the Lower Extremity Functional Scale (LEFS) questionnaires. Independent variables included demographics, injury characteristics, and the Mental Component Score (MCS) of the SF36. RESULTS: Greater mental health was independently and strongly associated with greater capability, independent of amputation or limb reconstruction. Mental health explained 33% of the variation in PCS and 57% of the variation in LEFS. Injury location at the knee or leg was associated with greater capability, compared to the foot or ankle. Amputation or limb reconstruction was not associated with capability. DISCUSSION: This study adds to the growing body of knowledge that physical health is best regarded through the lens of the bio-psycho-social model in which mental health is a strong determinant. This study supports making mental health an important aspect of rehabilitation after major lower extremity injury, regardless of amputation or limb salvage.

Clinical Results of Patients with Combined Aptis Distal Radioulnar Joint Arthroplasty and Total Wrist Arthroplasty.

Background Severely destroyed wrists can be managed by combined radiocarpal and distal radioulnar joint (DRUJ) replacement that reduces pain while mobility is ought to be reserved. The combination of these arthroplasties is rarely reported in the literature. Purpose This article describes the clinical outcomes of six consecutive patients with both total wrist and Aptis DRUJ arthroplasty with a median follow-up of 50 months (range: 18-108 months). Patients and Methods Patients with a TWA combined with an Aptis DRUJ arthroplasty were retrospectively identified. The patients were treated between 2011 and 2020. Results The flexion-extension arc was slightly decreased in three cases while forearm rotation was improved in three patients. Pain was adequately reduced in four patients and significant pain was seen in two patients. Although three of four patients could not return to previous work, all patients claimed to be satisfied with the result of the procedure. Conclusion This article demonstrates the possible feasibility of this combined arthroplasty in patients with a destroyed and unstable wrist. Level of Evidence Level III.

Patient-reported outcomes after free muscle flap coverage for therapy-resistant neuropathic pain from the ulnar nerve.

Extensive microsurgical neurolysis followed by free gracilis muscle flap coverage can be performed as a last resort for patients with persistent neuropathic pain of the ulnar nerve. All patients who had this surgery between 2015 and 2021 were identified. Data were collected from the medical records of 21 patients and patient-reported outcomes were collected from 18 patients, with a minimum follow-up of 12 months. The median visual analogue pain score decreased significantly 8 months postoperatively from 8.0 to 6.0 and stabilized to 5.4 at the 3-year follow-up. Health-related quality-of-life scores remained diminished compared to normative data. In the treatment of therapy-resistant neuropathic pain of the ulnar nerve, extensive neurolysis with a subsequent free gracilis muscle flap coverage shows a promising reduction of pain that persists at long-term follow-up.Level of evidence: IV.

Does Revision Carpal Tunnel Release Result in Long-Term Outcomes Equivalent to Single Carpal Tunnel Release? A Matched Case-Control Analysis.

BACKGROUND: The aims of this study were to evaluate long-term patient-reported outcomes after revision carpal tunnel release (CTR); compare these outcomes with those of patients who had a single CTR and a comparable age, sex, race, type of initial surgery, and follow-up time; and assess which factors are associated with worse patient-reported outcomes after revision CTR. METHODS: The authors retrospectively identified 7351 patients who had a single CTR and 113 patients who had a revision CTR for carpal tunnel syndrome between January of 2002 and December of 2015 at five academic urban hospitals. Of these 113 revision CTR cases, 37 patients completed a follow-up questionnaire including the Boston Carpal Tunnel Questionnaire (BCTQ), the Numerical Rating Scale for Pain Intensity, and satisfaction score. Those who completed the follow-up questionnaire were randomly matched to five controls (patients who had a single CTR) based on age, sex, race, type of initial surgery, and follow-up time. Of these 185 matched controls, 65 completed the follow-up questionnaire. RESULTS: A linear mixed effects model using matched sets as a random effect showed that patients who had a revision CTR had a higher total BCTQ score, Numerical Rating Scale for Pain Intensity score, and a lower satisfaction score at time of follow-up than patients who had a single CTR. Multivariable linear regression showed that thenar muscle atrophy before the revision surgery was independently associated with more pain after revision surgery. CONCLUSION: Patients improve after revision CTR, but generally have more pain, have a higher BCTQ score, and are less satisfied at long-term follow-up compared with patients who had a single CTR.

Mid-term outcomes of three commonly used surgical reconstructions for scapholunate instability.

This retrospective analysis reports the mid-term (>2 years) outcomes of capsulodesis, (modified) Brunelli tenodesis and bone-ligament-bone reconstruction for scapholunate ligament instability. In total, 60 patients (64 wrists) returned the Patient-Rated Wrist Evaluation and Disabilities of the Arm, Shoulder, and Hand questionnaires. Of these participants, 42 (46 wrists) returned for a wrist examination and radiographs. In the questionnaire group, the mean follow-up for capsulodesis was 11.8 years, tenodesis 5.9 years and bone-ligament-bone 8.9 years. In the objective outcomes group, the mean follow-up was 10.2 years for capsulodesis, 5.7 for tenodesis and 8.9 for bone-ligament-bone. In all groups, some patients showed radiographic deterioration, which did not always correlate with poor functional outcome. With a mean follow-up greater than 5 years, there was no substantial difference in clinical outcomes and patient-based outcome questionnaires between capsulodesis, tenodesis or bone-ligament-bone reconstruction for the treatment of scapholunate instability. This study emphasizes the need for further research. Surgeons should use the technique that produces the fewest complications.Level of evidence III.

[Lacertus syndrome, an unknown and underestimated diagnosis]. / Het lacertussyndroom.

BACKGROUND: Carpal tunnel syndrome (CTS) is well-known. Less familiar are proximal median nerve entrapments such as the lacertus syndrome. Lacertus syndrome symptoms are very similar to CTS, but often unknowledged. CASE DESCRIPTION: A 37 year old male with persistent tingling of the median nerve area after 3 CTS releases on both wrists. The diagnosis CTS was confirmed with EMG and ultrasound. In our outpatient clinic we saw weakness of the tip pinch (FPL, FDP2). Loss of sensibility in the proximal thenar and digits 1-3 and a positive scratch collapse test. We suspected the patient has lacertus syndrome and performed a lacertus release. All symptoms dissolved afterwards. CONCLUSION: If symptoms do not resolve after CTS-release proximal median nerve compressions should be considered. Tip pinch strength and sensibility of the thenar can differentiate between the various locations of median nerve entrapment. Redo CTS-release lead to unnecessary treatment and costs, because of the wrong diagnosis.

Decoding the Mastectomy SKIN Score: An Evaluation of Its Predictive Performance in Immediate Breast Reconstruction.

BACKGROUND: The skin ischemia and necrosis (SKIN) score was introduced to standardize the assessment of mastectomy skin flap necrosis (MSFN) severity and the need for reoperation. We evaluated the association between the SKIN score and the long-term postoperative outcomes of MSFN after mastectomy and immediate breast reconstruction (IBR). METHODS: We conducted a retrospective cohort study of consecutive patients who developed MSFN following mastectomy and IBR from January 2001 to January 2021. Primary outcome was breast-related complications following MSFN. Secondary outcomes were 30-day readmission, operating room (OR) debridement, and reoperation. Study outcomes were correlated with the SKIN composite score. RESULTS: We identified 299 reconstructions in 273 consecutive patients with mean follow-up time of 111.8±3.9 months. Most patients had a composite SKIN score of B2 (25.0%, n=13), followed by D2 (17.3%) and C2 (15.4%). We found no significant difference in rates of OR debridement (p=0.347), 30-day readmission (p=0.167), any complication (p=0.492), or reoperation for a complication (p=0.189) based on the SKIN composite score. The composite skin score was a poor predictor of reoperation, with area under the curve (AUC) of 0.56. A subgroup analysis in patients who underwent implant-based reconstruction revealed no difference in rates of OR debridement (p=0.986), 30-day readmission (p=0.530), any complication (p=0.492), or reoperation for a complication (p=0.655) based on the SKIN composite score. CONCLUSION: The SKIN score was a poor predictor for postoperative MSFN outcomes and reoperation. An individualized risk-assessment tool that incorporates both the anatomical appearance of the breast, imaging data, and patient-level risk factors is needed.

The Current Role of Arthroscopy in Traumatic Wrist Injuries: An Expert Survey.

Background Wrist arthroscopy has become increasingly popular for diagnosing and treating traumatic wrist injuries. How wrist arthroscopy has influenced the daily practice of wrist surgeons remains unclear. The objective of this study was to evaluate the role of wrist arthroscopy for the diagnosis and treatment of traumatic wrist injuries among members of the International Wrist Arthroscopy Society (IWAS). Methods An online survey was conducted among IWAS members between August and November 2021 with questions regarding the diagnostic and therapeutic importance of wrist arthroscopy. Questions focused on traumatic injuries of the triangular fibrocartilage complex (TFCC) and scapholunate ligament (SLL). Multiple-choice questions were presented in the form of a Likert scale. The primary outcome was respondent agreement, defined as 80% answering similarly. Results The survey was completed by 211 respondents (39% response rate). The majority (81%) were certified or fellowship-trained wrist surgeons. Most respondents (74%) had performed over 100 wrist arthroscopies. Agreement was reached on 4 of the 22 questions. It was agreed that the outcomes of wrist arthroscopy strongly depend on surgeons' experience, that there is sufficient evidence for the diagnostic purposes of wrist arthroscopy, and that wrist arthroscopy is better than magnetic resonance imaging (MRI) for diagnosing TFCC and SLL injuries. No agreement was reached on the preferred treatment of any type of TFCC or SLL injury. Conclusion There is agreement that wrist arthroscopy is superior to MRI for diagnosing traumatic TFCC and SLL injuries, yet experts remain divided on the optimal management. Guidelines need to be developed for the standardization of indications and procedures. Level of Evidence This is a Level III study.

A Systematic Review on Long-Term Postsurgical Pain Outcomes; What Is the Effect of Upper Extremity Regional Anesthesia?

BACKGROUND: Chronic pain is a recognized complication of surgery, and it has been hypothesized that regional anesthesia might reduce the risk of development of chronic pain after upper extremity surgery. METHODS: A systematic literature review was performed to assess whether in patients undergoing elective upper extremity surgery (P), regional anesthesia (I), compared to general anesthesia (C), would result in lower long-term (>3 months) postoperative pain intensity (O). We included randomized and nonrandomized controlled trials (RCTs). Our primary outcome was numerical rating score or visual analogue scale for pain, at >3 months postoperatively. The Embase, Medline ALL, Web of Science Core Collections, Cochrane Central Register of Controlled Trials, and Google Scholar databases were searched for all reports assessing pain at >3 months after upper extremity surgery under general versus regional anesthesia. Secondary outcomes were: opioid prescription filling, complex regional pain syndrome (CRPS) incidence, the Mayo Wrist Score (MWS), and scores on the Disability of the Arm, Shoulder and Hand (DASH) questionnaire. Quality (or certainty) of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Risk-of-bias was assessed using the Cochrane tool for randomized trials (RoB 2.0) and nonrandomized trials (ROBINS-I). RESULTS: This review included 14 studies, comprising 7 RCTs and 7 nonrandomized studies. Six of the 7 studies (4 RCTs, N = 273; 2 nonrandomized studies, N = 305) using a pain score, our primary outcome, report comparable long-term postoperative pain scores after regional and general anesthesia. Six of the 7 studies using our secondary outcomes report comparable long-term outcomes in terms of opioid prescription filling (2 retrospective cohort studies [RCSs], N = 89,256), CRPS incidence (1 RCT, N = 301), MWS (1 RCT and 1 RCS, N = 215), and DASH score (1 RCT, N = 36). Comparable outcomes were reported in all 7 RCTs (N = 778) and in 5 of the 7 nonrandomized studies, comprising 5 RCSs (N = 89,608). Two prospective observational studies (POSTs), comprising 279 patients, report a statistically significant difference in outcomes, with less pain and better DASH scores after brachial plexus anesthesia. All 14 studies provided moderate to very low certainty evidence, and there was a serious risk of bias due to confounding bias in 5 of the 7 nonrandomized studies (N = 631). CONCLUSIONS: The results of this review indicate that upper extremity regional anesthesia, compared to general anesthesia, is unlikely to change pain intensity at >3 months postoperatively.

Incidence of Chronic Postsurgical Pain after Upper Extremity Surgery and its Correlation with Preoperative Pain.

The incidence of chronic postsurgical pain (CPSP) after upper extremity surgery is not known. The goal was to study CPSP at 5 years postoperative and to investigate patient, surgical, and anesthetic risk factors. Methods: Patients scheduled for elective upper extremity surgery were included, and numeric rating scale (NRS) score for pain was obtained preoperatively and at 5 years postoperatively. According to the International Association for the Study of Pain definition, CPSP was defined as an increase in NRS compared with preoperatively. Results: A total 168 patients were contacted at 5 years postoperatively. Incidence of CPSP was 22%, and 35% had an NRS score of 4 or more. The number of patients with an NRS score of 0 and with an NRS score of 4 or more preoperatively was higher in the no-CPSP group, with P values of 0.019 and 0.008, respectively. Of the patients with no preoperative pain, 34% developed CPSP. Regional anesthesia was associated with a lower CPSP incidence (P = 0.001) and was more frequently applied in surgery on bony structures and in patients with a preoperative NRS score of 4 or more. Conclusions: The incidence CPSP was 22%. Patients with no pain or an NRS score of 4 or more preoperatively were less likely to develop CPSP, but individual susceptibility to pain and success of the surgery may be of influence. One-third of the patients with no preoperative pain developed CPSP. More studies are needed to reveal the exact relation between brachial plexus anesthesia and CPSP.

Human IAPP is a contributor to painful diabetic peripheral neuropathy.

Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage pancreatic islet ß cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth and increased levels of mitochondrial reactive oxygen species. hIAPP-transgenic mice, which have elevated plasma hIAPP levels without hyperglycemia, developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intraepidermal nerve fiber (IENF) density. Similarly, hIAPP Ob/Ob mice, which have hyperglycemia in combination with elevated plasma hIAPP levels, had signs of neuropathy, although more aggravated. In wild-type mice, intraplantar and intravenous hIAPP injections induced long-lasting allodynia and decreased IENF density. Non-aggregating murine IAPP, mutated hIAPP (pramlintide), or hIAPP with pharmacologically inhibited aggregation did not induce these effects. T2DM patients had reduced IENF density and more hIAPP oligomers in the skin compared with non-T2DM controls. Thus, we provide evidence that hIAPP aggregation is neurotoxic and mediates peripheral neuropathy in mice. The increased abundance of hIAPP aggregates in the skin of T2DM patients supports the notion that hIAPP is a potential contributor to T2DM neuropathy in humans.