Carpal Tunnel Syndrome and Trigger Finger May Be an Early Symptom of Preclinic Type 2 Diabetes.

Background: Type 2 diabetes (T2D) is a major risk factor for carpal tunnel syndrome (CTS) and trigger finger (TF), but less is known regarding the risk of developing T2D after being diagnosed with CTS or TF. CTS and TF could be early signs of preclinical T2D, and early detection of T2D is crucial to prevent complications and morbidity. Therefore, we investigate the association between CTS/TF and T2D in an adult population without previous T2D using big data registers in Sweden. Methods: Data were collected by crosslinking five nationwide Swedish registers. Individuals aged 40-85 years on December 31, 2010, without prior overt diabetes, were included (n = 3,948,517) and followed up from baseline (ie, a diagnosis of CTS or TF) or January 1, 2011, for controls, until a diagnosis of T2D, prescription of oral antidiabetics or insulin, or end of follow-up four years after baseline. Multivariate Cox regression models were created to calculate hazard ratios for T2D. Results: In total, 37,346 (0.95%) patients were diagnosed with CTS, whereof 1329 (3.46%) developed T2D. There were 17,432 (0.44%) patients who developed TF, whereof 639 (3.67%) developed T2D. Among the controls, 2.73% developed T2D. Compared with controls, there was an increased risk of developing T2D after being diagnosed with either CTS (HR 1.35; 95% confidence interval 1.28-1.43) or TF (HR 1.21; 95% confidence interval 1.12-1.31). Conclusion: Compared with controls, a diagnosis of CTS or TF was associated with 35% and 21% higher risk for later T2D, respectively, which might indicate the existence of undetected T2D in this population.

Muscle preservation in proximal nerve injuries: a current update.

Optimal recovery of muscle function after proximal nerve injuries remains a complex and challenging problem. After a nerve injury, alterations in the affected muscles lead to atrophy, and later degeneration and replacement by fat-fibrous tissues. At present, several different strategies for the preservation of skeletal muscle have been reported, including various sets of physical exercises, muscle massage, physical methods (e.g. electrical stimulation, magnetic field and laser stimulation, low-intensity pulsed ultrasound), medicines (e.g. nutrients, natural and chemical agents, anti-inflammatory and antioxidants, hormones, enzymes and enzyme inhibitors), regenerative medicine (e.g. growth factors, stem cells and microbiota) and surgical procedures (e.g. supercharge end-to-side neurotization). The present review will focus on methods that aimed to minimize the damage to muscles after denervation based on our present knowledge.

Surgery for carpal tunnel syndrome in patients with and without diabetes-Is there a difference in the frequency of surgical procedures?

Carpal tunnel syndrome (CTS) occurs more often among individuals with diabetes. The aim of this retrospective observational registry study was to examine whether individuals with diabetes and CTS are treated surgically to the same extent as individuals with CTS but without diabetes. Data on CTS diagnosis and surgery were collected from the Skåne Healthcare Register (SHR). A total of 35,105 individuals (age ≥ 18 years) diagnosed with CTS from 2004-2019 were included. Data were matched to the Swedish National Diabetes Register (NDR. Cox regression models were used to calculate the risk of the use of surgical treatment. Of the 35,105 included individuals with a CTS diagnosis, 17,662 (50%) were treated surgically, and 4,966 (14%) had diabetes. A higher number of individuals with diabetes were treated surgically (2,935/4,966, 59%) than individuals without diabetes (14,727/30,139, 49%). In the Cox regression model, diabetes remained a significant risk factor for surgical treatment (PR 1.14 (95% CI 1.11-1.17)). Individuals with type 1 diabetes were more frequently treated surgically (490/757, 65%) than individuals with type 2 diabetes (2,445/4,209, 58%). There was no difference between the sexes and their treatment. The duration of diabetes was also a risk factor for surgical treatment in diabetes type 2, but high HbA1c levels were not. Individuals with diabetes are more likely to be treated surgically for CTS than individuals without diabetes. Individuals with type 1 diabetes are more likely to be treated surgically for CTS than individuals with type 2 diabetes.

Carpal tunnel syndrome.

Carpal tunnel syndrome (CTS) is the most common nerve entrapment disorder worldwide. The epidemiology and risk factors, including family burden, for developing CTS are multi-factorial. Despite much research, its intricate pathophysiological mechanism(s) are not fully understood. An underlying subclinical neuropathy may indicate an increased susceptibility to developing CTS. Although surgery is often performed for CTS, clear international guidelines to indicate when to perform non-surgical or surgical treatment, based on stage and severity of CTS, remain to be elucidated. Neurophysiological examination, using electrophysiology or ultrasonography, performed in certain circumstances, should correlate with the history and findings in clinical examination of the person with CTS. History and clinical examination are particularly relevant globally owing to lack of other equipment. Various instruments are used to assess CTS and treatment outcomes as well as the effect of the disorder on quality of life. The surgical treatment options of CTS - open or endoscopic - offer an effective solution to mitigate functional impairments and pain. However, there are risks of post-operative persistent or recurrent symptoms, requiring meticulous diagnostic re-evaluation before any additional surgery. Health-care professionals should have increased awareness about CTS and all its implications. Future considerations of CTS include use of linked national registries to understand risk factors, explore possible screening methods, and evaluate diagnosis and treatment with a broader perspective beyond surgery, including psychological well-being.

The Unpredictable Ulnar Nerve-Ulnar Nerve Entrapment from Anatomical, Pathophysiological, and Biopsychosocial Aspects.

Peripheral nerves consist of delicate structures, including a rich microvascular system, that protect and nourish axons and associated Schwann cells. Nerves are sensitive to internal and external trauma, such as compression and stretching. Ulnar nerve entrapment, the second most prevalent nerve entrapment disorder after carpal tunnel syndrome, appears frequently at the elbow. Although often idiopathic, known risk factors, including obesity, smoking, diabetes, and vibration exposure, occur. It exists in all adult ages (mean age 40-50 years), but seldom affects individuals in their adolescence or younger. The patient population is heterogeneous with great co-morbidity, including other nerve entrapment disorders. Typical early symptoms are paresthesia and numbness in the ulnar fingers, followed by decreased sensory function and muscle weakness. Pre- and postoperative neuropathic pain is relatively common, independent of other symptom severity, with a risk for serious consequences. A multimodal treatment strategy is necessary. Mild to moderate symptoms are usually treated conservatively, while surgery is an option when conservative treatment fails or in severe cases. The decision to perform surgery might be difficult, and the outcome is unpredictable with the risk of complications. There is no consensus on the choice of surgical method, but simple decompression is relatively effective with a lower complication rate than transposition.

Round table discussion: the management of idiopathic cubital tunnel syndrome.

Idiopathic cubital tunnel syndrome is the second most common neuropathy in the upper limb. Best evidence regarding the surgical management of this condition has evolved from anterior or submuscular transposition as the former reference standard, to in situ simple release. Differences of opinion remain regarding the timing of surgery, type of surgery and adjunctive surgery. Four surgeons with Level 5 expertise were asked to answer specific questions regarding this condition.

Socioeconomic factors and outcome after repair and reconstruction of digital and major nerve trunk injuries in the upper limb.

Peripheral nerve injuries in the upper limb can lead to substantial disability and pain. We aimed to assess how socioeconomic factors affect outcomes after repaired or reconstructed digital or major nerve trunk injuries in the upper limb. We identified 670 individuals, who underwent surgical nerve repair or reconstruction using sensory nerve autografts, in the Swedish National Quality Registry for Hand Surgery 2010-2018. Socioeconomic factors, including education, cohabitation, type of work, sick leave, immigrant status and income, were gathered from the Swedish statistical agency ( www.scb.se ) and National Diabetes Register (NDR). We calculated prevalence ratios (PR) to assess the relationship between socioeconomic factors and surgical outcomes for the nerve injuries. Individuals with a major nerve trunk injury had higher QuickDASH scores and lower income compared to those with digital nerve injury. Individuals with immigration background (adjusted PR = 2.0, 95% CI 1.2-3.2), history of > 4 weeks of sick leave the year before surgery (adjusted PR = 1.8, 95% CI 1.1-3.1), or education level below tertiary (adjusted PR = 2.8, 95% CI 1.7-4.7) had significantly higher QuickDASH scores. Recognizing impact of non-biological factors, including immigration, prior sick leave, and education level, on outcome after nerve surgery is crucial for improving prognosis in socioeconomically deprived individuals.

Effects of socioeconomic status on patient-reported outcome after surgically treated trigger finger: a retrospective national registry-based study.

OBJECTIVES: To investigate if socioeconomic status impacts patient-reported outcomes after a surgically treated trigger finger (TF). DESIGN AND SETTING: Data on patients with TF treated with surgery were collected from the Swedish National Quality Registry of Hand Surgery (HAKIR) 2010-2019 with an evaluation of symptoms and disability before surgery and at 3 and 12 months after surgery, using the short version of the Disabilities of Arm, Shoulder and Hand (QuickDASH) questionnaire.Data from HAKIR and the Swedish National Diabetes Registry (ndr.nu) were combined with socioeconomic data from Statistics Sweden (scb.sc), analysing the impact of marital status, education level, income, occupation, sickness benefits, days of unemployment, social assistance and migrant status on the outcome by a linear regression model. PARTICIPANTS: In total, 5477 patients were operated on for primary TF during the study period, of whom 21% had diabetes, with a response rate of 35% preoperatively, 26% at 3 months and 25% at 12 months. RESULTS: At all time points, being born in Sweden (preoperatively B-coefficient: -9.74 (95% CI -13.38 to -6.11), 3 months postoperatively -9.80 (95% CI -13.82 to -5.78) and 12 months postoperatively -8.28 (95% CI -12.51 to -4.05); all p<0.001) and high earnings (preoperatively -7.81 (95% CI -11.50 to -4.12), 3 months postoperatively -9.35 (95% CI -13.30 to -5.40) and 12 months postoperatively -10.25 (95% CI -14.37 to -6.13); all p<0.0001) predicted lower QuickDASH scores (ie, fewer symptoms and disability) in the linear regression models. More sick leave during the surgery year predicted higher QuickDASH scores (preoperatively 5.77 (95% CI 3.28 to 8.25; p<0.001), 3 months postoperatively 4.40 (95% CI 1.59 to 7.22; p<0.001) and 12 months postoperatively 4.38 (95% CI 1.35 to 7.40; p=0.005)). No socioeconomic factors impacted the change in QuickDASH score from preoperative to 12 months postoperatively in the fully adjusted model. CONCLUSION: Individuals with low earnings, high sick leave the same year as the surgery and those born outside of Sweden reported more symptoms both before and after surgery, but the relative improvement was not affected by socioeconomic factors.

A self-managed exercise therapy program for wrist osteoarthritis: study protocol for a randomized controlled trial.

BACKGROUND: Post-traumatic wrist osteoarthritis (OA) can eventually lead to pain, muscular weakness, and stiffness of the wrist, which can affect the function of the entire upper limb and reduce the quality of life. Although there is strong evidence that all patients with OA should be offered adequate education and exercises as a first-line treatment, an effective self-management program, including structured education and therapeutic exercises, has not yet been introduced for individuals with wrist OA. This trial aims to evaluate the effectiveness of an exercise therapy program with joint protective strategies to improve neuromuscular control (intervention group) compared to a training program with range of motion exercises (control group). METHODS: This is a single-blinded randomized controlled trial (RCT) with two treatment arms in patients with symptomatic and radiographically confirmed wrist OA. The trial will be conducted at a hand surgery department. The participants will be randomly assigned either to a neuromuscular exercise therapy program or to a training program with range of motion exercises only. Participants in both groups will receive a wrist orthosis and structured education on wrist anatomy, pathophysiology, and joint protective self-management strategies. The programs consist of home exercises that will be performed twice a day for 12 weeks. The Patient-Rated Wrist Evaluation (PRWE) is the primary outcome measure of pain and function. Wrist range of motion (ROM), grip strength, the Numeric Pain Rating scale (NPRS), Disabilities of the Arm, Shoulder, and Hand (DASH), the General Self-Efficacy Scale (GSES), Global Rating of Change (GROC), and conversion to surgery are the secondary measures of outcome. Assessments will be performed at baseline and at 3, 6, and 12 months after baseline by a blinded assessor. DISCUSSION: The upcoming results from this trial may add new knowledge about the effectiveness of a self-managed exercise therapy program on pain and function for individuals with wrist OA. If the present self-management program proves to be effective, it can redefine current treatment strategies and may be implemented in wrist OA treatment protocols. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05367817. Retrospectively registered on 27 April 2022. https://clinicaltrials.gov .

Surgery of Schwannoma in the upper limb - sensitivity and specificity of preoperative magnetic resonance imaging and relation between tumour size and symptoms.

BACKGROUND: Benign peripheral nerve tumours consist of different types, most commonly Schwannomas. Preoperative Magnetic Resonance Imaging (MRI) is commonly performed before surgery and Pathoanatomical Diagnosis (PAD) confirms the diagnosis. Our aims were to study the utility of MRI and the relation between tumour size and symptoms. METHODS: Retrospectively, patients, surgically treated for benign nerve tumours between 2008 and 2019, were identified and preoperative MRI, with measurement of tumour size, PAD, symptoms, peroperative details, and symptomatic outcomes of surgery, were analysed. RESULTS: The sensitivity and specificity to correctly identify Schwannomas with preoperative MRI were 85% and 50%, respectively, based on 30 Schwannomas and nine neurofibromas that were identified. Tumour size did not affect the presence of preoperative symptoms, but patients with sensory dysfunction at last follow-up had larger Schwannomas (p < 0.05). Symptoms as a palpable tumour, paraesthesia and pain improved by surgical excision (p < 0.001, p < 0.001 and p < 0.012, respectively), but sensory and motor dysfunction were common postoperatively. No malignant peripheral nerve sheath tumours (MPNST) were found. Using a surgical microscope, instead of only loop magnification, lowered the risk of perioperative nerve injuries (p < 0.05), but did not further diminish postoperative symptoms. CONCLUSIONS: Early and accurate diagnosis of Schwannomas is valuable for adequate presurgical preparation and prompt surgical intervention. Preoperative examination with MRI has a high sensitivity, but low specificity; although recent advancement in MRI technology indicates improvement in diagnostic precision. Surgical excision is preferably performed early in conjunction with symptomatic debut to improve outcome.

Neuromas cause severe residual problems at long-term despite surgery.

Pain, and disabilities after neuroma surgery, using patient reported outcome measurements (PROMs), were evaluated by QuickDASH and a specific Hand Questionnaire (HQ-8). The 69 responding individuals (response rate 61%; 59% women; 41% men; median follow up 51 months) reported high QuickDASH score, pain on load, cold sensitivity, ability to perform daily activities and sleeping difficulties. Individuals reporting impaired ability to perform daily activities and sleeping problems had higher scores for pain, stiffness, weakness, numbness/tingling, cold sensitivity and QuickDASH. Only 17% of individuals reported no limitations at all. No differences were observed between sexes. Surgical methods did not influence outcome. Symptoms and disabilities correlated moderately-strongly to each other and to ability to perform regular daily activities as well as to sleeping difficulties. Pain, cold sensitivity, sleeping difficulties and limitation to perform daily activities were associated to higher QuickDASH. A weak association was found between follow up time and QuickDASH score as well as pain on load, but not cold sensitivity. A major nerve injury was frequent among those with limitations during work/performing other regular daily activities. Despite surgical treatment, neuromas cause residual problems, which affect the capacity to perform daily activities and ability to sleep with limited improvement in long-term.

Overuse of the psychoactive analgesics' opioids and gabapentinoid drugs in patients having surgery for nerve entrapment disorders.

Knowledge about risks for overuse of psychoactive analgesics in patients having primary surgery for carpal tunnel syndrome (CTS) or ulnar nerve entrapment (UNE), or both, is limited. We investigated if patients with those nerve entrapment disorders have a higher risk of overuse of psychoactive analgesics (i.e., opioids and gabapentinoid drugs) before, after, and both before and after surgery than observed in the general population after accounting for demographical and socioeconomic factors. Using a large record linkage database, we analysed 5,966,444 individuals (25-80 years), residing in Sweden December 31st, 2010-2014, of which 31,380 underwent surgery 2011-2013 for CTS, UNE, or both, applying logistic regression to estimate relative risk (RR) and 95% confidence interval (CI). Overall, overuse of the psychoactive analgesics was low in the general population. Compared to those individuals, unadjusted RR (95% CI) of overuse ranged in patients between 2.77 (2.57-3.00) with CTS after surgery and 6.21 (4.27-9.02) with both UNE and CTS after surgery. These risks were only slightly reduced after adjustment for demographical and socioeconomic factors. Patients undergoing surgery for CTS, UNE, or both, have a high risk of overuse of psychoactive analgesics before, after, and both before and after surgery.

The retinacular ligaments of the digital extensor expansion revisited: An anatomical and biomechanical study.

Our aim was to clarify the anatomy and function of the retinacular ligaments. Forty-eight fingers were dissected and the thickness of the oblique retinacular ligament (ORL) was graded. In four fingers, the motion in the proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints was subjected to an in-depth analysis before and after sectioning of either the lateral bands (LB) or the ORLs. The function of the ORLs in restricting flexion of the DIP joint with full extension of the PIP joint was measured in 10 fingers. An ORL could be identified on both sides in all 48 fingers. The distribution of the insertion on the proximal phalanx was 7/96 (7%) in the distal third, 70/96 (73%) in the middle third and 19/96 (20%) in the proximal third. Among the specimens, 29% were graded as having a strong bundle of fibers, 51% as having well-defined and regular fibers and 20% as having thin and sparse fibers. With the PIP joint extended, there was a statistically significant increase in flexion of the DIP joint after the ORL was cut. After the LB was sectioned, the ORL was able to extend the DIP joint with an extension lag of 10-22°. Cutting the ORL did not affect the ability to extend that joint. We conclude that the retinacular ligaments are consistent. Their major role is not connected with finger movement, but to provide stabilizing links between the PIP and DIP joints. They are active in not only specific, uncommon finger positions but also in ordinary use of the fingers.

Benign nerve tumours in the upper limb: a registry-based study of symptoms and surgical outcome.

Surgery for benign nerve tumours is performed for pathoanatomical diagnosis and symptomatic relief, but might cause residual problems. We aimed to assess patient-reported symptoms and disability before and after surgery at a national level. In total, 206 cases surgically treated for a benign peripheral nerve tumour 2010-2019 registered in the Swedish Quality Registry for Hand Surgery (HAKIR; response rates 22-34%) were analysed. Surgery reduced overall disability in the affected limb (QuickDASH 18/100 [IQR 5-36] preoperatively and 5/100 [IQR 0-22] 12 months postoperatively), improved ability to perform daily activities (HQ-8; 11/100 [IQR 0-50] preoperatively and 0/100 [IQR 0-20] 12 months postoperatively) and decreased three evaluated pain modalities: pain at rest (HQ-8; 20/100 [IQR 0-40] preoperatively and 0/100 [IQR 0-10] 12 months postoperatively), pain on motion without load (HQ-8; 20/100 [IQR 0-40] preoperatively and 0/100 [IQR 0-10] 12 months postoperatively), and pain on load (HQ-8; 24/100 [IQR 1-69] preoperatively and 1/100 [IQR 0-30] 12 months postoperatively). Cold sensitivity was a minor problem both before and after surgery (HQ-8; 0/100 [IQR 0-30] preoperatively and 1/100 [IQR 0-40] 12 months postoperatively). We conclude that surgery for benign peripheral nerve tumours provides good symptomatic relief with low risk for residual problems.

Exposure to hand-held vibrating tools and biomarkers of nerve injury in plasma: a population-based, observational study.

OBJECTIVES: To analyse potential biomarkers for vibration-induced nerve damage in a population-based, observational study. DESIGN: Prospective cohort study. SETTING: Malmö Diet Cancer Study (MDCS), Malmö, Sweden. PARTICIPANTS: In a subcohort of 3898 individuals (recruited 1991-1996) from MDCS (baseline examination in 28 449 individuals; collection of fasting blood samples in a cardiovascular subcohort of MDCS of 5540 subjects), neuropathy-relevant plasma biomarkers were analysed during follow-up after filling out questionnaires, including a question whether work involved hand-held vibrating tools, graded as 'not at all', 'some' or 'much'. PRIMARY OUTCOME MEASURES: The neuropathy-relevant plasma biomarkers vascular endothelial growth factor (VEGF)-A, VEGF-D, VEGF receptor 2, galanin, galectin-3, HSP27, ß-nerve growth factor, caspase-3, caspase-8, transforming growth factor-α and tumour necrosis factor were analysed. Data were analysed by conventional statistics (Kruskal-Wallis test; post hoc test Mann-Whitney U test; Bonferroni correction for multiple testing) and in a subanalysis for galanin using two linear regression models (unadjusted and adjusted). RESULTS: Among participants, 3361 of 3898 (86%) reported no work with hand-held vibrating tools, 351 of 3898 (9%) reported some and 186 of 3898 (5%) much work. There were more men and smokers in vibration-exposed groups. Galanin levels were higher after much vibration exposure (arbitrary units 5.16±0.71) compared with no vibration exposure (5.01±0.76; p=0.015) with no other observed differences. CONCLUSIONS: Higher plasma levels of galanin, possibly related to magnitude, frequency, acceleration and duration, as well as to severity of symptoms of vibration exposure, may be found in individuals working with hand-held vibrating tools.

Evaluation of Processed Nerve Allograft in Peripheral Nerve Surgery: A Systematic Review and Critical Appraisal.

Peripheral nerve injuries cause substantial problems when not treated properly. A specific problem is reconstruction of nerve defects, which can be treated in different ways. This study aimed to systematically review whether processed nerve allograft (PNA) is justified in reconstruction of a nerve defect in patients after posttraumatic or iatrogenic peripheral nerve injury and to compare PNA with other established methods. Methods: A systematic review with a focused question, PICO (patient, intervention, comparison, outcome) and constraints, was performed. A structured literature search, including several databases, was done to evaluate the existing evidence for outcomes and postoperative complications related to PNA. The certainty of evidence was classified according to Grading of Recommendations, Assessment, Development and Evaluations. Results: No conclusions, concerning differences in outcome of nerve reconstruction using PNA compared with the use of nerve autograft or conduits, could be drawn. The level of certainty for all evaluated outcomes was very low (⊕◯◯◯). Most published studies lack a control group to patients treated with PNA; being only descriptive, making it difficult to compare PNA with established methods without substantial risk of bias. For studies including a control group, the scientific evidence was of very low certainty, due to a low number of included patients, and large, undefined loss of patients during follow-up, rendering a high risk of bias. Finally, the authors often had financial disclosures. Conclusion: Properly conducted randomized controlled trial studies on the use of PNA in reconstruction of peripheral nerve injuries are needed to establish recommendations in clinical practice.

Patient Experiences after Open Trigger Finger Release in Patients with Type 1 and Type 2 Diabetes-A Retrospective Study Using Patient-reported Outcome Measures.

Trigger finger is overrepresented among patients with diabetes mellitus (DM). Whether DM affects the outcome after open trigger finger release (OTFR) in patients with DM is not known. Our aim was thus to explore outcomes after OTFR in patients with type 1 (T1D) and type 2 DM (T2D). Methods: Data included patient-reported outcome measures (PROMs) from all OTFRs performed between 2010 and 2020 registered in the Swedish national registry for hand surgery in individuals over 18 years cross-linked with the Swedish National Diabetes Register (NDR). PROMs included QuickDASH and HQ8, a questionnaire designed for national registry for hand surgery, preoperative and at 3 and 12 months postoperative. HQ8 included pain on load, pain on motion without load, and stiffness. Outcome was calculated using linear-mixed models and presented as means adjusted for age and stratified by sex. Results: In total, 6242 OTFRs were included, whereof 496 had T1D (332, 67% women) and 869 had T2D (451, 52% women). Women with T1D reported more symptoms of stiffness (P < 0.001), and women with T2D reported more pain on load (P < 0.05), motion without load (P < 0.01), and worse overall result at 3 months. At 12 months, however, no differences were found in any of the HQ-8 PROMs among men or women. Women with T2D had slightly higher QuickDASH scores at 3 and 12 months. Conclusion: Patients with T1D and T2D can expect the same results after OTFR as individuals without DM, although the improvement might take longer especially among women with T2D.

Comparison of Novel Wide-Field In Vivo Corneal Confocal Microscopy With Skin Biopsy for Assessing Peripheral Neuropathy in Type 2 Diabetes.

Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes, where skin biopsy assessing intraepidermal nerve fiber density (IENFD) plays an important diagnostic role. In vivo confocal microscopy (IVCM) of the corneal subbasal nerve plexus has been proposed as a noninvasive diagnostic modality for DPN. Direct comparisons of skin biopsy and IVCM in controlled cohorts are lacking, as IVCM relies on subjective selection of images depicting only 0.2% of the nerve plexus. We compared these diagnostic modalities in a fixed-age cohort of 41 participants with type 2 diabetes and 36 healthy participants using machine algorithms to create wide-field image mosaics and quantify nerves in an area 37 times the size of prior studies to avoid human bias. In the same participants, and at the same time point, no correlation between IENFD and corneal nerve density was found. Corneal nerve density did not correlate with clinical measures of DPN, including neuropathy symptom and disability scores, nerve conduction studies, or quantitative sensory tests. Our findings indicate that corneal and intraepidermal nerves likely mirror different aspects of nerve degeneration, where only intraepidermal nerves appear to reflect the clinical status of DPN, suggesting that scrutiny is warranted concerning methodologies of studies using corneal nerves to assess DPN. ARTICLE HIGHLIGHTS: Comparison of intraepidermal nerve fiber density with automated wide-field corneal nerve fiber density in participants with type 2 diabetes revealed no correlation between these parameters. Intraepidermal and corneal nerve fibers both detected neurodegeneration in type 2 diabetes, but only intraepidermal nerve fibers were associated with clinical measures of diabetic peripheral neuropathy. A lack of association of corneal nerves with peripheral neuropathy measures suggests that corneal nerve fibers may be a poor biomarker for diabetic peripheral neuropathy.

Bioengineered nerve conduits and wraps for peripheral nerve repair of the upper limb.

BACKGROUND: Traumatic peripheral nerve injury is common and incurs significant cost to individuals and society. Healing following direct nerve repair or repair with autograft is slow and can be incomplete. Several bioengineered nerve wraps or devices have become available as an alternative to direct repair or autologous nerve graft. Nerve wraps attempt to reduce axonal escape across a direct repair site and nerve devices negate the need for a donor site defect, required by an autologous nerve graft. Comparative evidence to guide clinicians in their potential use is lacking. We collated existing evidence to guide the clinical application of currently available nerve wraps and conduits. OBJECTIVES: To assess and compare the effects and complication rates of licensed bioengineered nerve conduits or wraps for surgical repair of traumatic peripheral nerve injuries of the upper limb. To compare effects and complications against the current gold surgical standard (direct repair or nerve autograft). SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search was 26 January 2022. We searched online and, where not accessible, contacted societies' secretariats to review abstracts from the British Surgical Society of the Hand, International Federation of Surgical Societies of the Hand, Federation of European Surgical Societies of the Hand, and the American Society for Peripheral Nerve from October 2007 to October 2018. SELECTION CRITERIA: We included parallel group randomised controlled trials (RCTs) and quasi-RCTs of nerve repair in the upper limb using a bioengineered wrap or conduit, with at least 12 months of follow-up. DATA COLLECTION AND ANALYSIS: We used standard Cochrane procedures. Our primary outcomes were 1. muscle strength and 2. sensory recovery at 24 months or more. Our secondary outcomes were 3. British Medical Research Council (BMRC) grading, 4. integrated functional outcome (Rosén Model Instrument (RMI)), 5. touch threshold, 6. two-point discrimination, 7. cold intolerance, 8. impact on daily living measured using the Disability of Arm Shoulder and Hand Patient-Reported Outcome Measure (DASH-PROM), 9. sensory nerve action potential, 10. cost of the device, and 11. adverse events (any and specific serious adverse events (further surgery)). We used GRADE to assess the certainty of the evidence. MAIN RESULTS: Five studies involving 213 participants and 257 nerve injuries reconstructed with wraps or conduits (129 participants) or standard repair (128 participants) met the inclusion criteria. Of those in the standard repair group, 119 nerve injuries were managed with direct epineurial repair, and nine autologous nerve grafts were performed. One study excluded the outcome data for the repair using an autologous nerve graft from their analysis, as it was the only autologous nerve graft in the study, so data were available for 127 standard repairs. There was variation in the functional outcome measures reported and the time postoperatively at which they were recorded. Mean sensory recovery, assessed with BMRC sensory grading (range S0 to S4, higher score considered better) was 0.03 points higher in the device group (range 0.43 lower to 0.49 higher; 1 RCT, 28 participants; very low-certainty evidence) than in the standard repair group (mean 2.75 points), which suggested little or no difference between the groups, but the evidence is very uncertain. There may be little or no difference at 24 months in mean touch thresholds between standard repair (0.81) and repair using devices, which was 0.01 higher but this evidence is also very uncertain (95% confidence interval (CI) 0.06 lower to 0.08 higher; 1 trial, 32 participants; very low-certainty evidence). Data were not available to assess BMRC motor grading at 24 months or more. Repair using bioengineered devices may not improve integrated functional outcome scores at 24 months more than standard techniques, as assessed by the Rosén Model Instrument (RMI; range 0 to 3, higher scores better); the CIs allow for both no important difference and a better outcome with standard repair (mean RMI 1.875), compared to the device group (0.17 lower, 95% CI 0.38 lower to 0.05 higher; P = 0.13; 2 trials, 60 participants; low-certainty evidence). Data from one study suggested that the five-year postoperative outcome of RMI may be slightly improved after repair using a device (mean difference (MD) 0.23, 95% CI 0.07 to 0.38; 1 trial, 28 participants; low-certainty evidence). No studies measured impact on daily living using DASH-PROM. The proportion of people with adverse events may be greater with nerve wraps or conduits than with standard techniques, but the evidence is very uncertain (risk ratio (RR) 7.15, 95% CI 1.74 to 29.42; 5 RCTs, 213 participants; very low-certainty evidence). This corresponds to 10 adverse events per 1000 people in the standard repair group and 68 per 1000 (95% CI 17 to 280) in the device group. The use of nerve repair devices may be associated with a greater need for revision surgery but this evidence is also very uncertain (12/129 device repairs required revision surgery (removal) versus 0/127 standard repairs; RR 7.61, 95% CI 1.48 to 39.02; 5 RCTs, 256 nerve repairs; very low-certainty evidence). AUTHORS' CONCLUSIONS: Based on the available evidence, this review does not support use of currently available nerve repair devices over standard repair. There is significant heterogeneity in participants, injury pattern, repair timing, and outcome measures and their timing across studies of nerve repair using bioengineered devices, which make comparisons unreliable. Studies were generally small and at high or unclear risk of bias. These factors render the overall certainty of evidence for any outcome low or very low. The data reviewed here provide some evidence that more people may experience adverse events with use of currently available bioengineered devices than with standard repair techniques, and the need for revision surgery may also be greater. The evidence for sensory recovery is very uncertain and there are no data for muscle strength at 24 months (our primary outcome measures). We need further trials, adhering to a minimum standard of outcome reporting (with at least 12 months' follow-up, including integrated sensorimotor evaluation and patient-reported outcomes) to provide high-certainty evidence and facilitate more detailed analysis of effectiveness of emerging, increasingly sophisticated, bioengineered repair devices.