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Our aim was to explore possible relationships between serum levels of biomarkers in patients with hand-arm vibration injury in relation to the severity of the vascular, i.e., Raynaud's phenomenon (RP), and neurosensory manifestations, the current exposure level, and the duration of exposure. This study was of case series design and involved 92 patients diagnosed with hand-arm vibration injury. Jonckheere's trend test was used to assess any association between serum levels of biomarkers and RP as well as neurosensory manifestations, graded by the International Consensus Criteria. Generalized linear models with adjustment for possible confounders were also used for associations between serum levels of biomarkers and; (1) severity of RP recorded as the extent of finger blanching calculated with Griffin score, (2) vibration perception thresholds, (3) magnitude of current exposure as [A(8); (m/s 2 )] value, and (4) the duration of exposure in years. Serum levels of thrombomodulin, von Willebrand factor, calcitonin gene related peptide (CGRP), heat shock protein 27, and caspase-3 were positively associated with severity of RP. Serum levels of CGRP were positively associated with the neurosensory component. No associations with exposure were shown for these biomarkers. For Intercellular adhesion molecule 1 and monocyte chemoattractant protein 1, no associations were found with neither severity nor exposure. Levels of serum biomarkers associated with endothelial injury or dysfunction, inflammation, vasodilation, neuroprotection, and apoptosis were positively associated with the severity of hand-arm vibration injury., (© 2024. The Author(s).)

Diabetes mellitus (DM) is a risk factor for the development of ulnar nerve entrapment (UNE). Differences in surgical outcomes for UNE between patients with and without DM have been reported, but studies on presurgical management are scarce. This study aimed to evaluate the presurgical management of UNE in patients with (DM diagnosis < 2 years of UNE diagnosis) and without DM regarding the level of care for diagnosis and the proportion that proceeds to surgery. Data from 6600 patients with UNE between 2004 and 2019 were included from the Skåne Health Care Register (SHR) and cross-linked with data from the Swedish National Diabetes Register (NDR). The group with UNE and DM was compared to the group with UNE without DM and prevalence ratios were calculated using Cox regression analysis. Patients with DM more often got their first UNE diagnosis in secondary care than in primary care (643/667, 96% vs. 5361/5786; 93%). Patients with and without DM, regardless of the type of DM, presence of retinopathy, or HbA1c levels, were surgically treated for UNE to the same extent (258/667, 39% of patients with DM vs. 2131/5786, 37% of patients without DM). The proportion of surgically treated was significantly lower among patients diagnosed with UNE in primary care compared to secondary care (59/449, 13% vs. 2330/5786, 38%). Men were more often surgically treated than women (1228/3191, 38% vs.1161/3262 36%). Patients with UNE and DM are surgically treated to the same extent as patients with UNE but without DM and are more likely to be diagnosed in specialized care., (© 2024. The Author(s).)

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., (© 2024. Springer Nature Limited.)

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., (© 2024. The Author(s).)

Hand-arm vibration injury is a well-known occupational disorder that affects many workers globally. The diagnosis is based mainly on quantitative psychophysical tests and medical history. Typical manifestations of hand-arm vibration injury entail episodes of finger blanching, Raynaud's phenomenon (RP) and sensorineural symptoms from affected nerve fibres and mechanoreceptors in the skin. Differences in serum levels of 17 different biomarkers between 92 patients with hand-arm vibration injury and 51 controls were analysed. Patients with hand-arm vibration injury entailing RP and sensorineural manifestations showed elevated levels of biomarkers associated with endothelial injury or dysfunction, inflammation, vaso- or neuroprotective compensatory, or apoptotic mechanisms: intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1); thrombomodulin (TM), heat shock protein 27 (HSP27); von Willebrand factor, calcitonin gene-related peptide (CGRP) and caspase-3. This study adds important knowledge on pathophysiological mechanisms that can contribute to the implementation of a more objective method for diagnosis of hand-arm vibration injury., (© 2024. The Author(s).)

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., (© 2023. Springer Nature Limited.)

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., (© 2023. Springer Nature Limited.)

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., (© 2023. The Author(s).)

Ulnar nerve compression at the elbow (UNE) frequently affects people of working age. Surgically treated patients may not immediately return to work (RTW) postoperatively. In 2008, the Swedish Social Insurance Agency reformed the national insurance policy. We aimed to examine RTW postoperatively for UNE, variations among surgical methods, and potential risk factors for prolonged RTW (sick leave > 6 weeks). Surgically treated cases of UNE (n = 635) from two time periods (2004-2008 and 2009-2014) and two healthcare regions (Southern and South-eastern) were studied retrospectively regarding age, sex, comorbidities, occupation, type of surgery and time to RTW. A sub-analysis of the exact number of weeks before RTW (n = 201) revealed longer RTW for unemployed cases compared to employed cases. Prolonged RTW was seen among younger, manual workers and after transposition or revision surgery. Prolonged RTW was approximately four times more likely after transposition than after simple decompression. Comparisons before and after 2008 showed occupational differences and differences in RTW, where cases operated before 2008 more often had permanent sickness benefit, but the reform of the social insurance system did not seem to influence RTW. In conclusion, unemployment, younger age at surgery, manual labour, transposition, and revision surgery were related to prolonged RTW., (© 2022. The Author(s).)

To investigate self-reported cold sensitivity and functional disability after a repaired digital nerve injury. We identified 3204 individuals operated with digital nerve repair in the Swedish national quality registry for hand surgery (HAKIR). Patient-reported symptoms, including cold sensitivity and perceived disability, were examined using two questionnaires (HQ-8 and QuickDASH), three and 12 months postoperatively. Patients with diabetes (n = 48; 3%) were identified in the Swedish National Diabetes Register (NDR). Cold sensitivity (scored 0-100) was the most prominent symptom among 1553 included individuals (998 men, 555 women; median age 41 [IQR 27-54] years). In the regression analysis, flexor tendon injury, hand fracture and injury to multiple structures predicted worsened cold sensitivity (6.9, 15.5 and 25.0 points; p = 0.005, 0.046 and < 0.001) at 12 months. Individuals with moderate (30-70) and severe (> 70) cold sensitivity had higher QuickDASH scores at three and 12 months postoperatively than individuals with mild cold sensitivity (6.0 and 5.5; 19.8 and 21.0 points; p = 0.001). Flexor tendon injury, injuries to multiple structures and diabetes had significant effect on QuickDASH scores at three, but not at 12, months postoperatively. Cold sensitivity is common after a digital nerve repair and impacts self-reported disability. A concomitant injury, particularly multiple injuries, predicts postoperative cold sensitivity., (© 2022. The Author(s).)

Dupuytren's disease (DD) is a fibroproliferative disorder affecting the palmar fascia of the hand. Risk factors include diabetes mellitus (DM), whereas a high body mass index (BMI) is associated with a lower prevalence of DD. The aim of this study was to further elucidate risk and protective factors for the development of DD using longitudinal population-based data from the Malmö Diet and Cancer Study (MDCS). During 1991-1996, the inhabitants aged 46-73 years in the city of Malmö, Sweden were invited to participate in the population-based MDCS (41% participation rate). Data on incident DD were retrieved from Swedish national registers. Associations between DM, alcohol consumption, BMI, and serum apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) at baseline were analysed in multivariable Cox regression models adjusted for known confounders. Among 30,446 recruited participants, 347 men and 194 women were diagnosed with DD during a median follow-up time of 23 years. DM (men HR 2.23; 95% CI 1.50-3.30, women HR 2.69; 95% CI 1.48-4.90) and alcohol consumption (men HR 2.46; 95% CI 1.85-3.27, women HR 3.56; 95% CI 1.95-6.50) were independently associated with incident DD in the Cox regression models. Furthermore, inverse associations with incident DD were found for obesity among men, and ApoB/ApoA1 ratio among both sexes. DM and excess alcohol consumption constituted major risk factors for the development of DD. Furthermore, an inverse association between obesity among men and DD, and also between ApoB/ApoA1 ratio and DD was found in both sexes., (© 2021. The Author(s).)

The study aimed to investigate socioeconomic factors in patients with carpal tunnel syndrome (CTS) and to evaluate their impact on outcome following open carpal tunnel release (OCTR). Data from the National Quality Register for Hand Surgery were combined with socioeconomic data (marital status, education level, earnings, migrant status, occupation, sick leave, unemployment, and social assistance) from Statistics Sweden to evaluate OCTRs performed from 2010 to 2016 (total 10,746 OCTRs). Patients completed QuickDASH (short version of Disabilities of Arm, Shoulder and Hand) questionnaires preoperatively (n = 3597) and at three (n = 2824) and 12 months (n = 2037) postoperatively. The effect of socioeconomic factors on QuickDASH scores was analyzed with linear regression analysis. Socioeconomically deprived patients scored higher on the QuickDASH on all occasions than patients with higher socioeconomic status. Being widowed, having a low education level, low earnings, immigrant status, frequent sick leave and dependence on social assistance all increased the postoperative QuickDASH score at 12 months. The change in total score for QuickDASH between preoperative and 12 months postoperatively did not vary between the groups. We conclude that such factors as being widowed, having a lower education level, low earnings, immigrant status, frequent sick leave and social assistance dependence are associated with more symptoms both before and after OCTR for CTS, but these factors do not affect the relative improvement in QuickDASH.

Cold sensitivity is common following nerve injuries in the upper extremity, but is less well studied in carpal tunnel syndrome (CTS). We investigated cold sensitivity in CTS and its effects on surgical outcome. A search of the Swedish National Registry for Hand Surgery (HAKIR) for open carpal tunnel releases (OCTR) from 2010-2016 identified 10,746 cases. Symptom severity questionnaires (HQ-8; HAKIR questionnaire 8, eight Likert-scale items scored 0-100, one item on cold sensitivity) and QuickDASH scores before and after surgery were collected. Patient mean age was 56 ± SD 16 years, and 7,150/10,746 (67%) were women. Patients with severe cold sensitivity (defined as cold intolerance symptom severity score > 70; n = 951), scored significantly higher on QuickDASH at all time points compared to those with mild cold sensitivity (cold intolerance symptom severity scores ≤ 30, n = 1,532); preoperatively 64 [50-75] vs. 40 [25-55], at three months 32 [14-52] vs. 18 [9-32] and at 12 months 25 [7-50] vs. 9 [2-23]; all p < 0.0001. Severe cold sensitivity predicted higher postoperative QuickDASH scores at three [12.9 points (95% CI 10.2-15.6; p < 0.0001)] and at 12 months [14.8 points (11.3-18.4; p < 0.0001)] compared to mild cold sensitivity, and adjustment for a concomitant condition in the hand/arm, including ulnar nerve compression, did not influence the results. Cold sensitivity improves after OCTR. A higher preoperative degree of cold sensitivity is associated with more preoperative and postoperative disability and symptoms than a lower degree of cold sensitivity, but with the same improvement in QuickDASH score.

A deeper knowledge of the architecture of the peripheral nerve with three-dimensional (3D) imaging of the nerve tissue at the sub-cellular scale may contribute to unravel the pathophysiology of neuropathy. Here we demonstrate the feasibility of X-ray phase contrast holographic nanotomography to enable 3D imaging of nerves at high resolution, while covering a relatively large tissue volume. We show various subcomponents of human peripheral nerves in biopsies from patients with type 1 and 2 diabetes and in a healthy subject. Together with well-organized, parallel myelinated nerve fibres we show regenerative clusters with twisted nerve fibres, a sprouted axon from a node of Ranvier and other specific details. A novel 3D construction (with movie created) of a node of Ranvier with end segment of a degenerated axon and sprout of a regenerated one is captured. Many of these architectural elements are not described in the literature. Thus, X-ray phase contrast holographic nanotomography enables identifying specific morphological structures in 3D in peripheral nerve biopsies from a healthy subject and from patients with type 1 and 2 diabetes.

Electrospinning can be used to mimic the architecture of an acellular nerve graft, combining microfibers for guidance, and pores for cellular infiltration. We made electrospun nerve guides, from polycaprolactone (PCL) or poly-L-lactic acid (PLLA), with aligned fibers along the insides of the channels and random fibers around them. We bridged a 10 mm rat sciatic nerve defect with the guides, and, in selected groups, added a cell transplant derived from autologous stromal vascular fraction (SVF). For control, we compared to hollow silicone tubes; or autologous nerve grafts. PCL nerve guides had a high degree of autotomy (8/43 rats), a negative indicator with respect to future usefulness, while PLLA supported axonal regeneration, but did not outperform autologous nerve grafts. Transplanted cells survived in the PLLA nerve guides, but axonal regeneration was not enhanced as compared to nerve guides alone. The inflammatory response was partially enhanced by the transplanted cells in PLLA nerve grafts; Schwann cells were poorly distributed compared to nerve guide without cells. Tailor-made electrospun nerve guides support axonal regeneration in vivo, and can act as vehicles for co-transplanted cells. Our results motivate further studies exploring novel nerve guides and the effect of stromal cell-derived factors on nerve generation.

Type 2 diabetes mellitus is characterized by a low-grade inflammation; however, mechanisms leading to this inflammation in specific tissues are not well understood. The eye can be affected by diabetes; thus, we hypothesized that inflammatory changes in the eye may parallel the inflammation that develops with diabetes. Here, we developed a non-invasive means to monitor the status of inflammatory dendritic cell (DC) subsets in the corneal epithelium as a potential biomarker for the onset of inflammation in type 2 diabetes. In an age-matched cohort of 81 individuals with normal and impaired glucose tolerance and type 2 diabetes, DCs were quantified from wide-area maps of the corneal epithelial sub-basal plexus, obtained using clinical in vivo confocal microscopy (IVCM). With the onset of diabetes, the proportion of mature, antigen-presenting DCs increased and became organized in clusters. Out of 92 plasma proteins analysed in the cohort, tumor necrosis factor receptor super family member 9 (TNFRSF9) was associated with the observed maturation of DCs from an immature to mature antigen-presenting phenotype. A low-grade ocular surface inflammation observed in this study, where resident immature dendritic cells are transformed into mature antigen-presenting cells in the corneal epithelium, is a process putatively associated with TNFRSF9 signalling and may occur early in the development of type 2 diabetes. IVCM enables this process to be monitored non-invasively in the eye.

A dense nerve plexus in the clear outer window of the eye, the cornea, can be imaged in vivo to enable non-invasive monitoring of peripheral nerve degeneration in diabetes. However, a limited field of view of corneal nerves, operator-dependent image quality, and subjective image sampling methods have led to difficulty in establishing robust diagnostic measures relating to the progression of diabetes and its complications. Here, we use machine-based algorithms to provide wide-area mosaics of the cornea's subbasal nerve plexus (SBP) also accounting for depth (axial) fluctuation of the plexus. Degradation of the SBP with age has been mitigated as a confounding factor by providing a dataset comprising healthy and type 2 diabetes subjects of the same age. To maximize reuse, the dataset includes bilateral eye data, associated clinical parameters, and machine-generated SBP nerve density values obtained through automatic segmentation and nerve tracing algorithms. The dataset can be used to examine nerve degradation patterns to develop tools to non-invasively monitor diabetes progression while avoiding narrow-field imaging and image selection biases.