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BackgroundThere is potential for adverse events from corticosteroid injections, including increase in blood glucose, decrease in bone mineral density and suppression of the hypothalamic-pituitary axis. Published studies note that doses lower than those commonly injected provide similar benefit.MethodsDevelopment of the practice guideline was approved by the Board of Directors of American Society of Regional Anesthesia and Pain Medicine with several other societies agreeing to participate. The scope of guidelines was agreed on to include safety of the injection technique (landmark-guided, ultrasound or radiology-aided injections); effect of the addition of the corticosteroid on the efficacy of the injectate (local anesthetic or saline); and adverse events related to the injection. Based on preliminary discussions, it was decided to structure the topics into three separate guidelines as follows: (1) sympathetic, peripheral nerve blocks and trigger point injections; (2) joints; and (3) neuraxial, facet, sacroiliac joints and related topics (vaccine and anticoagulants). Experts were assigned topics to perform a comprehensive review of the literature and to draft statements and recommendations, which were refined and voted for consensus (≥75% agreement) using a modified Delphi process. The United States Preventive Services Task Force grading of evidence and strength of recommendation was followed.ResultsThis guideline deals with the use and safety of corticosteroid injections for sympathetic, peripheral nerve blocks and trigger point injections for adult chronic pain conditions. All the statements and recommendations were approved by all participants after four rounds of discussion. The Practice Guidelines Committees and Board of Directors of the participating societies also approved all the statements and recommendations. The safety of some procedures, including stellate blocks, lower extremity peripheral nerve blocks and some sites of trigger point injections, is improved by imaging guidance. The addition of non-particulate corticosteroid to the local anesthetic is beneficial in cluster headaches but not in other types of headaches. Corticosteroid may provide additional benefit in transverse abdominal plane blocks and ilioinguinal/iliohypogastric nerve blocks in postherniorrhaphy pain but there is no evidence for pudendal nerve blocks. There is minimal benefit for the use of corticosteroids in trigger point injections.ConclusionsIn this practice guideline, we provided recommendations on the use of corticosteroids in sympathetic blocks, peripheral nerve blocks, and trigger point injections to assist clinicians in making informed decisions.

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

BACKGROUND: Unanticipated symptoms of peripheral nerve damage following surgery are distressing to both the patient and their clinical team, including surgeons, anesthesiologists, and neurologists. The causes that are commonly considered for perioperative neuropathy can include surgical trauma, positioning-related injury, or injury related to a regional anesthetic technique. However, these cases often do not have a clear etiology and can occur without any apparent periprocedural anomalies. Postoperative inflammatory neuropathy is a more recently described, and potentially underrecognized cause of perioperative neuropathy which may improve with corticosteroid therapy. Therefore, it is an important etiology to consider early in the evaluation of perioperative neuropathy. CASE PRESENTATION: An otherwise healthy patient presented for left anterior cruciate ligament reconstruction. He underwent femoral and sciatic ultrasound-guided single-injection peripheral nerve blocks preoperatively, followed by a general anesthetic for the surgical procedure. He developed postoperative neuropathy in the sciatic distribution with both sensory and motor deficits. The patient received multi-disciplinary consultations, including neurology and pain management, and a broad differential diagnosis was considered. Based on neurological evaluation and imaging studies, a final diagnosis of post-surgical inflammatory neuropathy was made. The patients course improved with conservative management, but immunosuppressive treatment may have been considered for a more severe or worsening clinical course. CONCLUSIONS: There are limited publications describing postoperative inflammatory neuropathy, and this case serves to illustrate a potentially under-recognized and multifactorial cause of postoperative neuropathy. Perioperative neuropathies are a complication that surgeons and anesthesiologists strive to avoid; however, prevention and treatment of this condition have been elusive. Increased reporting and investigation of postoperative inflammatory neuropathy as one cause for this complication will help to further our understanding of this potentially devastating complication.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) and its associated pain negatively affect patient outcomes and quality of life (QoL). The two-part MiroCIP study included interventional and prospective observational studies. Here, we report the latter, describing CIPN incidence, risk factors, and outcomes. Research design and methods: This 1-year, multicenter, prospective registry study (May 2021–April 2023) included patients aged ≥ 20 years with colorectal, gastric, non-small cell lung, or breast cancer who were scheduled to undergo chemotherapy with oxaliplatin or taxane. The primary endpoint was Grade ≥ 2 sensory CIPN incidence within 12 months after chemotherapy initiation. Subjective and objective symptoms, QoL, and pain were evaluated. Results: Overall, 216 patients (female, 64.4%; mean age, 60.3 years) were included. Ninety-one (42.1%) and 131 (60.6%) patients received oxaliplatin- and taxane-based chemotherapy, respectively (six received both and were included in both groups). Grade ≥ 2 CIPN occurred in 96 patients (44.4%; 72.8/100 person-years), with 70.8% (68/96 patients) developing symptoms within 90 days. The most prominent CIPN symptoms were limb numbness/tingling and decreased vibration sensibility. No clinically meaningful risk factors were identified. Conclusions: We clarified CIPN incidence in cancer patients. Subjective symptoms (limb numbness/tingling, decreased vibration sensibility) and pain are important CIPN symptoms requiring careful monitoring. Trial registration: jRCTs031210101. [ABSTRACT FROM AUTHOR]

Background: Both vitamin B6 deficiency and vitamin B12 deficiency can present with symptoms that appear like polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome, with painful peripheral neuropathy and sensorimotor dysfunction. There are rare reports of an association between vitamin B12 deficiency and POEMS syndrome, and even rarer reports of an association between vitamin B6 deficiency and POEMS syndrome. To our knowledge, this is the first described case with deficiencies in both vitamin B6 and vitamin B12 in association with POEMS syndrome. Case presentation: A man in his 40s presented with fatigue, imbalance, and painful numbness and tingling. Initial evaluation revealed low vitamin B12 level, and he received oral and IV supplementation for one month with an improvement in vitamin B12 levels, but without improvement in symptoms. Further evaluation revealed both a vitamin B6 deficiency and an IgA lambda monoclonal spike, prompting further investigation and an eventual diagnosis of POEMS syndrome. He underwent an autologous stem cell transplant and has had improvement in his symptoms. Conclusions: Patients with POEMS syndrome may have symptoms that are difficult to distinguish from deficiencies in vitamin B6 or vitamin B12. Management of POEMS should include screening of vitamin B6 and B12 to ensure other possible associated causes of symptoms are appropriately treated. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of chemotherapy. The objective of this prospective observational study was to examine the association between circadian misalignment (CM), as measured by phase angle difference (PAD) of biological and behavioral rhythms and CIPN. The PAD of cortisol acrophase and actigraphy-based sleep end time in breast cancer patients was measured and categorized into low PAD (n = 11) and high PAD (n = 12) groups based on median value. CIPN was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN20 (CIPN20). The assessment of CM revealed that the sleep end time of the low PAD group was more delayed in relation to cortisol acrophase compared to the high PAD group. The low PAD group demonstrated significantly higher CIPN20 global and sensory scale scores compared to the high-PAD group at one month post-chemotherapy, with an estimated group difference of 17.63 ± 4.75 and 27.07 ± 6.70 (p = 0.001 and p < 0.001, respectively). The present findings indicate that the low PAD group, which exhibited a relatively delayed behavioral rhythm with respect to its biological rhythm, displayed an increased susceptibility to CIPN. Further large-sample research is necessary to attain a comprehensive understanding of the mechanisms through which CM affects CIPN. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association of hypersensitive cardiac troponin (hs-cTnT), a biomarker of myocardial injury, with diabetic lower extremity disease in American adults. Methods: We conducted a cross-sectional study (unweighted N=1,196) of diabetic patients aged 40 years or older who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. Logistic regression was used to assess the association of hs-cTnT with lower extremity disease, including peripheral neuropathy (as assessed by monofilament test), peripheral artery disease (as assessed by ankle-brachial index), history of foot ulcers, or amputation. All analyses are weighted. Results: The prevalence rate of diabetic lower extremity disease was 41.6%. Adjusted hs-cTnT was significantly associated with lower limb disease in adults with diabetes. There is interaction between chronic kidney disease and hs-cTnT, which strongly interferes with the correlation between hs-cTnT and lower extremity lesions in diabetic patients. Conclusions: Our study suggests the usefulness of hs-cTnT as a biomarker for lower extremity lesions in adults with diabetes and highlights the potential direct interaction of hs-cTnT with chronic kidney disease. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and severe side effect affecting cancer patients undergoing paclitaxel treatment. Growing evidence underscores the pivotal role of calcitonin-related peptide (CGRP) in the development of CIPN. Repeated administration of paclitaxel induces alterations in CGRP release from sensory neurons within the dorsal root ganglia (DRG). The density of the CGRP receptor is most prominent in the dorsal horn of the spinal cord, where it overlaps with the distribution of CGRP. However, the impact of chemotherapy treatment on expression of the CGRP receptor in the spinal cord remains unclear, as well as the potential therapeutic benefits of a CGRP receptor antagonist in an animal model of CIPN. Using a mouse model of paclitaxel-induced mechanical hypersensitivity, we show upregulation of Calcitonin receptor-like receptor (Calcrl) mRNA expression in the spinal cord, an event that occurred in association with upregulation of the H3K4 methyltransferase MLL2. This effect of repeated paclitaxel administration was also linked to an increase in the recruitment of MLL2, thereby enhancing levels of the active mark H3K4me2 at the Calcrl promoter. Furthermore, administration of the CGRP receptor antagonist BIBN4096 mitigated mechanical and cold hypersensitivity in paclitaxel-treated mice. Together, these observations suggest the CGRP receptor in the spinal cord as a potential target for reducing paclitaxel-induced neuropathic pain in animal models. [ABSTRACT FROM AUTHOR]

Background/Objectives: Docetaxel is a cytotoxic agent for the treatment of breast cancer, and its toxicities include peripheral neuropathy (PN). This study evaluated the ability of frozen sock (FS) treatment to prevent docetaxel-induced PN by performing nerve conduction study (NCS). Methods: From October 2017 to October 2018, 48 patients who had invasive carcinoma and were planned for docetaxel treatment every three weeks were evaluated. Patients wore a FS on the right foot, and the left foot was not protected by the FS during docetaxel infusion. Motor and sensory NCS as well as nail and skin toxicities were assessed. Results: The amplitude and velocity of the motor and sensory nerves significantly decreased after three months in both feet. Before and after three months of chemotherapy, the compound motor action potentials (CMAPs) for the right peroneal nerve were 7.64 ± 2.42 and 6.81 ± 2.21 mV, respectively (p < 0.001), and 7.13 ± 2.41 and 5.90 ± 2.24 mV, respectively (p < 0.001), for the left peroneal nerve. Reductions in the CMAP amplitude of the peroneal nerve were significantly lower in the right foot compared to the left foot (−9.58 vs. −16.8, p = 0.043). Application of the FS did not significantly decrease the overall incidence of skin and nail toxicity compared with the left foot during the study period (all p > 0.05). Conclusions: Docetaxel induced motor and sensory PN, but the use of a FS resulted in a smaller reduction in peroneal nerve amplification three months after the end of chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether short-term wear of textured insoles alters balance, gait, foot sensation, physical activity, or patient-reported outcomes, in people with diabetic neuropathy. Materials and Methods: 53 adults with diabetic neuropathy were randomised to wear textured or smooth insoles for 4-weeks. At baseline and post-intervention, balance (foam/firm surface; eyes open/closed) and walking were assessed whilst barefoot, wearing shoes only, and two insoles (textured/smooth). The primary outcome was center of pressure (CoP) total sway velocity. Secondary outcomes included other CoP measures, spatiotemporal gait measures, foot sensation, physical activity, and patient-reported outcomes (foot health, falls efficacy). Results: Wearing textured insoles led to improvements in CoP measures when standing on foam with eyes open, relative to smooth insoles (p ≤ 0.04). The intervention group demonstrated a 5% reduction in total sway velocity, indicative of greater balance. The intervention group also showed a 9-point improvement in self-perceived vigour (p = 0.03). Adjustments for multiple comparisons were not applied. Conclusions: This study provides weak statistical evidence in favour of textured insoles. Wearing textured insoles may alter measures of balance, suggestive of greater stability, in people with diabetic neuropathy. Plantar stimulation, through textured insoles, may have the capacity to modulate the perception of foot pain, leading to improved well-being. IMPLICATIONS FOR REHABILITATION: Short-term wear of textured insoles can lead to improvements in centre of pressure sway measures when standing on a compliant supporting surface. Wearing textured insoles may have the capacity to help relieve foot pain leading to enhanced self-perceived vitality in people with diabetic peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Introduction Acute pain in cancer is an important but often overlooked feature of many patients' oncological journey. Cancer-related pain is associated commonly with more persistent pain states caused by both the disease and its treatment, but there are numerous causes of acute pain which can develop in patients with cancer. This pain is frequently severe, can be challenging to manage and its suboptimal control can directly impact on oncological outcomes. This narrative review provides an overview of several causes of acute pain in patients with cancer and management approaches. Methods A focused literature review was conducted to encompass the search terms 'acute pain', 'oncology' and 'cancer' in adult and paediatric populations. Results Acute pain is common in patients with cancer with a number of pain generators identified. Broadly, these are disease- and treatment-related but commonality in pain mechanisms and features are present. Importantly, these pain states do not occur in isolation; a patient may experience multiple acute pain episodes during their oncology journey. Discussion As the oncological treatment landscape shifts and increasing numbers of novel treatments are employed, the number of causes of acute pain in patients with cancer rises. This pain is often managed by non-pain specialists and suboptimal control has a variety of deleterious effects. It is important that awareness of acute pain in the oncological population is increased and treatment approaches, which adopt a biopsychosocial structure, are optimised. [ABSTRACT FROM AUTHOR]

Polyneuropathies are common, with the incidence increasing with older age. The causes of polyneuropathies are diverse and numerous, and it can be challenging for clinicians to determine the etiology of a particular patient's neuropathy. In this article, we systematically detail a practical approach to polyneuropathies, beginning with the most important aspects of the workup, the history and physical. We then discuss the limited diagnostic approach required for patients who present with a distal symmetric polyneuropathy and the more comprehensive approach for patients who present with other neuropathy subtypes. [ABSTRACT FROM AUTHOR]

Uncommon mononeuropathies are challenging to diagnose as they can mimic joint pathology, radiculopathies, or plexopathies. They are less easily diagnosed due to unfamiliarity with their clinical presentation, knowledge of anatomy, and less commonly used diagnostic studies. A careful history, physical examination, and electrodiagnostic evaluation can help identify these neuropathies in a timely manner to administer the best treatment for resolution of symptoms. Recent advances in ultrasound and magnetic resonance techniques are used to confirm clinical suspicion of peripheral neuropathy by clearly depicting the anatomy and pathology as well as describing findings that mimic mononeuropathy. It is important for neurology, orthopedic, rheumatology, emergency, and primary care physicians to be familiar with less common mononeuropathies. [ABSTRACT FROM AUTHOR]

A 50-year-old woman with a 20-year history of gait instability presented with new-onset vertigo and oscillopsia. Examination revealed bilateral vestibular loss, cerebellar ataxia, sensory neuropathy, a “yes-yes” head tremor, nystagmus and a family history of a similar syndrome. Genetic testing for cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (RFC1) was negative, but whole exome sequencing identified a novel mutation in the DNA methyltransferase 1 (DNMT1) gene, broadening the differential diagnosis for this phenotype. Management was focused on symptomatic treatment and genetic counseling. This case highlights the importance of considering DNMT1 mutations in patients with a similar clinical presentation. [ABSTRACT FROM AUTHOR]

Purpose: Peripheral neuropathy is one of the most devastating symptoms experienced by the patients. Supportive and holistic care interventions are crucial to help these patients. The aim of this study is to determine the effects of hand and foot exercises on chemotherapy-induced peripheral neuropathy and quality of life in women with breast cancer. Methods: The sample of this randomized controlled trial study consisted of 79 women with breast cancer who underwent taxane-group chemotherapy in a hospital. The women diagnosed with grade 1 or higher peripheral neuropathy were included in the study. Women were divided into three groups as exercises with a massage ball, exercises with a stress ball, and control group. Hand and foot exercises last for 8 weeks. Data were collected using the Information Form, the Common Terminology Criteria for Adverse Events, and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire. Results: The severity of neuropathy decreased significantly in both massage ball and stress ball exercise groups compared to the control group (p < 0.05). The group and time interaction was statistically significant in fatigue, pain, and motor symptoms (p < 0.05). Conclusion: Women with breast cancer who undergo neurotoxic chemotherapy are thought to alleviate neuropathy symptoms and enhance their quality of life through simple home-based exercises. Nonpharmacological, applicable interventions, such as hand-foot exercises, can be integrated into patient education and care practices during the chemotherapy process. Trial registration: ClinicalTrails.gov (Registration number: NCT06055088. registered on 01 June 2023). [ABSTRACT FROM AUTHOR]

Background and Objective: Neuronal intranuclear inclusion disease (NIID) is a multifaceted disorder impacting both the central and peripheral nervous systems. This study aims to investigate the clinical and electrophysiological characteristics of peripheral neuropathy in patients with NIID. Methods: In this cross-sectional study, patients diagnosed with NIID were prospectively recruited from multiple centers across China between October 2017 and May 2024. Comprehensive neurological examinations, brain magnetic resonance imaging, and NOTCH2NLC gene analysis were performed. All participants underwent electrophysiological evaluations, which encompassed nerve conduction studies, F-wave studies, and needle electromyography. Results: This analysis included a total of 78 patients diagnosed with NIID, with a mean age of 61.0 ± 9.9 years, of whom 60.2% were female. Among these patients, 85.9% exhibited peripheral neuropathy. Specifically, 19 patients (24.4%) presented with symptomatic peripheral neuropathy, with 17 of these individuals demonstrating sensorimotor polyneuropathy. Additionally, 48 patients (61.5%) exhibited subclinical peripheral nerve damage. Segmental motor conduction studies indicated that both distal and proximal nerve segments were uniformly affected. F-wave latency prolongation was observed in 84.6% of tibial nerves, demonstrating high sensitivity (66/67) and specificity (11/11) for detecting peripheral neuropathy in NIID. The severity of peripheral neuropathy was stratified into four levels, with approximately two-thirds of cases presenting with pure demyelination and one-third displaying a combination of demyelination and axonal degeneration. Severe axonal damage was exclusively identified in the neuromuscular disease-dominant subtype of NIID. Importantly, male patients exhibited more pronounced peripheral nerve damage compared to female patients. Conclusions: This study identified a significant prevalence of peripheral neuropathy in NIID, exhibiting a spectrum of severity ranging from mild demyelination to severe axonal damage. Prolongation of F-wave latency emerged as a sensitive marker for the detection of peripheral nerve impairment. Furthermore, the findings underscore the potential influence of gender in the pathophysiology of NIID, warranting further investigation. [ABSTRACT FROM AUTHOR]

Aims Quantification of cardiac [99mTc]-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) uptake enhances diagnostic capabilities and may facilitate prognostic stratification in patients with transthyretin cardiac amyloidosis (ATTR-CA). This study aimed to evaluate the association of quantitative left ventricular (LV) DPD uptake with myocardial structure and function, and their implications on outcome in ATTR-CA. Methods and results Consecutive ATTR-CA patients (n = 100) undergoing planar DPD scintigraphy with Perugini grade 2 or 3, alongside quantitative DPD single-photon emission computed tomography/computed tomography imaging and speckle-tracking echocardiography between 2019 and 2023, were included and divided into two cohorts based on median DPD retention index (low DPD uptake: ≤5.4, n = 50; high DPD uptake: >5.4, n = 50). The DPD retention index showed significant, albeit weak to modest, correlations with LV global longitudinal strain (LV-GLS: r = 0.366, P < 0.001), right ventricular free wall longitudinal strain (RV-FW-LS: r = 0.316, P = 0.002), LV diastolic function (E/e′ average: r = 0.304, P = 0.013), NT-proBNP (r = 0.332, P < 0.001), troponin T (r = 0.233, P = 0.022), 6 min walk distance (6MWD: r = −0.222, P = 0.033), and National Amyloidosis Centre (NAC) stage (r = 0.294, P = 0.003). ATTR-CA patients in the high DPD uptake cohort demonstrated more advanced disease severity regarding longitudinal cardiac function (LV-GLS: P = 0.012, RV-FW-LS: P = 0.036), LV diastolic function (E/e′ average: P = 0.035), cardiac biomarkers (NT-proBNP: P = 0.012, troponin T: P = 0.044), exercise capacity (6MWD: P = 0.035), and disease stage (NAC stage I: P = 0.045, III: P = 0.006), and experienced adverse outcomes compared with the low DPD uptake cohort [composite endpoint: all-cause death or heart failure hospitalization, HR: 2.873 (95% CI: 1.439–5.737), P = 0.003; DPD retention index: adjusted HR 1.221 (95% CI: 1.078–1.383), P = 0.002]. Conclusion In ATTR-CA, enhanced quantitative LV DPD uptake indicates advanced disease severity and is associated with adverse outcome. DPD quantification may facilitate prognostic stratification when diagnosing patients with ATTR-CA. [ABSTRACT FROM AUTHOR]

PURPOSE: Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting toxicity of paclitaxel in patients with cancer. TIPN prediction is challenging although patients with higher systemic paclitaxel exposure have higher TIPN risk. This study aimed to identify protein predictors of TIPN and paclitaxel pharmacokinetics (PK). METHODS: This is a retrospective analysis of a prospective study of females with early-stage breast cancer receiving weekly paclitaxel. TIPN was assessed using the sensory subscale of the European Organisation for Research and Treatment of Cancer QLQ-Chemotherapy-Induced Peripheral Neuropathy (CIPN)20 (CIPN8). A blood sample was collected within 10 minutes before the end of the first paclitaxel infusion to measure plasma proteins using liquid chromatography-mass spectrometry and to estimate maximum systemic paclitaxel concentration (C max). A second sample was collected approximately 24 hours after the first infusion to estimate paclitaxel time above threshold (T c >0.05). Linear mixed-effect and regression models were used to identify proteins predictive of TIPN and paclitaxel PK parameters, respectively, using a Bonferroni-adjusted α =.0006. RESULTS: Data from 36 participants were included in the analysis testing associations of 83 proteins with TIPN or PK. Higher levels of complement C3 were associated with more severe TIPN trajectories (P =.0002). No proteins were associated with either C max or T c >0.05 (all P >.0006). CONCLUSION: Complement C3 concentration at the end of initial paclitaxel infusion may be useful for identifying patients with breast cancer and potentially other tumor types who could benefit from TIPN prevention strategies to improve long-term treatment outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Peripheral neuropathy (PN) is the most common neurodegenerative disorder, and the primary causes are chemotherapy-induced peripheral neuropathy (CIPN) and diabetic neuropathy (DN). Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising non-pharmacological and non-invasive intervention that targets key pathways involved with PN. However, research is needed to determine the feasibility, acceptability, and effects of taVNS in people with PN. It is also critical that this research on taVNS include the perspectives of Black and Hispanic/Latino patients, who are often underrepresented in research. Methods: This research was comprised of two consecutive studies: a survey and a pilot randomized sham-controlled trial (RCT). The survey assessed symptom burden, management strategies, and interest in taVNS among CIPN patients. The pilot RCT evaluated the feasibility, acceptability, and preliminary effects of taVNS in Black and Hispanic/Latino patients with CIPN or diabetic neuropathy. Participants were recruited from the University of Miami medical system, with culturally sensitive approaches to enhance minority participation. Results: The survey included 62 respondents, 78% Black or Hispanic/Latino, revealing high symptom burden and significant interest in taVNS (82% expressed moderate to high interest). The pilot RCT enrolled 28 participants, achieving a 42% recruitment rate and 86% retention. taVNS was well tolerated, with no significant adverse effects. Preliminary data indicated a decrease in neuropathic symptoms and an increased heart rate variability (HRV) during active taVNS, suggesting autonomic modulation. Tingling sensation and pain decreased by median values of 2.0 and 1.5, respectively. Additionally, the median values for standard deviation of the RR interval increased from 34.9 (CI = 21.6–44.8) at baseline to 44.8 (CI = 26.5–50.3) during intervention. Exit interviews highlighted positive participant experiences and identified potential barriers, such as protocol length and distrust in medical research. Conclusion: The findings underscore the need for novel CIPN treatments and demonstrate the feasibility of conducting taVNS research in historically underrepresented populations. High interest in taVNS and successful recruitment and retention rates suggest that culturally sensitive approaches can enhance minority participation in clinical trials. These findings will be used to develop a large clinical trial to determine the efficacy of repeated taVNS in a diverse cohort. Clinical Trial Registration: https://clinicaltrials.gov , identifier (NCT05896202). [ABSTRACT FROM AUTHOR]

Objective: Cubital tunnel syndrome is a common peripheral neuropathy of the upper extremity. Anterior transposition of the ulnar nerve is an established surgical treatment option for this condition. This study aimed to introduce a novel musculofascial lengthening technique that uses only a portion of the flexor-pronator muscle mass for submuscular anterior transposition of the ulnar nerve and investigate its clinical outcomes. Methods: We evaluated 28 patients (29 cases; 1 patient had bilateral involvement) diagnosed with cubital tunnel syndrome who were treated with surgical decompression and submuscular anterior transposition of the ulnar nerve using our novel technique. Mean follow-up was 19.1 months (range, 12–31). Patient-reported outcomes were assessed using the Boston Carpal Tunnel Questionnaire (BCTQ), Disabilities of the Arm, Shoulder, and Hand (DASH) Questionnaire, and numeric rating scale (NRS) for pain. Objective outcomes including light touch perception, static two-point discrimination, and grip strength were also assessed. Modified Bishop score and postoperative complications were also evaluated. Results: BCTQ symptom severity and functional status scores, DASH score, and NRS for pain score showed significant improvement after surgery. Light touch perception, static two-point discrimination, and grip strength also significantly improved after surgery. All patients showed excellent or good results according to the modified Bishop scoring system. No recurrence or complications occurred. Conclusion: Our novel musculofascial lengthening technique that uses only a portion of the flexor-pronator muscle mass for submuscular anterior transposition of the ulnar nerve reliably achieves good results with minimal complications in patients with cubital tunnel syndrome. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma (MM) with Guillain-Barré syndrome (GBS) is relatively rare, and the specific mechanism is still unclear. The previous infection, surgery, and medication use may have contributed to the occurrence of GBS. The use of bortezomib in patients with MM can easily lead to peripheral neuropathy, which is similar to the symptoms of GBS, making it challenging to diagnose GBS. Cases presentation: Three patients with IgA type MM experienced lower limb weakness during treatment. Combined with lumbar puncture, nerve conduction studies, and other tests, the diagnosis was confirmed as GBS. All three patients had a history of spinal surgery before the onset of GBS, and had been treated with bortezomib which induced peripheral neuropathy. Two of the three patients had a clear history of upper respiratory tract infection before the onset of GBS. After treatment with intravenous immunoglobulin, one patient died and two patients showed improvement in GBS symptoms. Conclusion: Patients with MM often have concurrent infections and spinal surgery, which may contribute to the occurrence of GBS. The symptoms of bortezomib-induce peripheral neuropathy overlap with those of GBS, which can easily lead to misdiagnosis or missed diagnosis of GBS. Timely lumbar puncture and nerve conduction studies may help to diagnose GBS and improve the prognosis. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the effects of spinal cord stimulation (SCS) on pain, neuropathic symptoms, and other health-related metrics in patients with chronic painful peripheral neuropathy (PN) from multiple etiologies. Methods: A prospective single center observational longitudinal cohort study assessed SCS efficacy from April 2023 to May 2024, with follow-ups at 2, 4, 6, and 12 months in 19 patients suffering from the painful polyneuropathy of diverse etiologies: diabetic (DPN), idiopathic (CIAP), chemotherapy-induced (CIPN), and others. Patients were implanted with a neurostimulator (WaveWriter AlphaTM, Boston Scientific Corporation, Valencia, CA, USA) and percutaneous leads targeting the lower limbs (T10–T11) and, if necessary, the upper limbs (C4–C7). Stimulation programming was individualized based on patient preference and best response. Assessments were performed before and after implantation and included pain intensity (VAS and DN4), neuropathic pain symptoms (NPSI and SF-MPQ-2), autonomic symptoms (SFN-SIQ and SAS), sensory and small fiber nerve injury (UENS), functionality (GAF), sleep (CPSI), global impression of change (CGI and PGI), and quality of life (EQ-VAS and EQ-5D). Intra-epidermal nerve fiber density (IENFD) via skin biopsy was also performed at baseline (diagnostic) and after 12 months to assess potential small fiber re-growth. Statistical analyses were conducted to determine the evolution of treatment success. Results: To date, 19 patients have undergone implantation and completed follow-up. SCS produced a significant consistent and sustained improvement in pain intensity by 49% in DN4 and 76% in VAS, in neuropathic pain symptoms by 73%, in autonomic symptoms by 26–30%, in the sensorimotor physical exam by 8%, in functionality by 44%, in sleep by 74%, and in quality of life (69% for EQ-VAS and 134% EQ-5D). Both clinicians and patients had a meaningful global impression of change, at 1.1 and 1.3, respectively. Distal intra-epidermal nerve fiber density improved by 22% at 12 months while proximal intra-epidermal nerve fiber density decreased by 18%. Conclusions: SCS is an effective therapy for managing various types of PN. [ABSTRACT FROM AUTHOR]

Peripherin belongs to heterogeneous class III of intermediate filaments, and it is the only intermediate filament protein selectively expressed in the neurons of the peripheral nervous system. It has been previously discovered that peripherin interacts with proteins important for the endo-lysosomal system and for the transport to late endosomes and lysosomes, such as RAB7A and AP-3, although little is known about its role in the endocytic pathway. Here, we show that peripherin silencing affects lysosomal abundance but also positioning, causing the redistribution of lysosomes from the perinuclear area to the cell periphery. Moreover, peripherin silencing affects lysosomal activity, inhibiting EGFR degradation and the degradation of a fluorogenic substrate for proteases. Furthermore, we demonstrate that peripherin silencing affects lysosomal biogenesis by reducing the TFEB and TFE3 contents. Finally, in peripherin-depleted cells, the autophagic flux is strongly inhibited. Therefore, these data indicate that peripherin has an important role in regulating lysosomal biogenesis, and positioning and functions of lysosomes, affecting both the endocytic and autophagic pathways. Considering that peripherin is the most abundant intermediate filament protein of peripheral neurons, its dysregulation, affecting its functions, could be involved in the onset of several neurodegenerative diseases of the peripheral nervous system characterized by alterations in the endocytic and/or autophagic pathways. [ABSTRACT FROM AUTHOR]

Background: Paclitaxel-induced peripheral neuropathy (PIPN) is prevalent among patients receiving paclitaxel chemotherapy, which results in sensory abnormality as well as neuropathic pain. Conventional medications lack effectiveness on PIPN. Clinical trials identified beneficial effects of acupuncture on PIPN among patients receiving chemotherapy. Here we explored the mechanisms underlying how acupuncture might alleviate PIPN. Methods: A mouse model of PIPN was established by repeated paclitaxel application. Electroacupuncture (EA) was applied at ST36 and BL60 acupoints of model mice. Immunostaining, flow cytometry, behavioral assay, in vivo imaging were utilized for effects determination and mechanism exploration. Results: EA ameliorated mechanical and cold pain hypersensitivities, reduced sensory neuron damage and improved loss in intra-epidermal nerve fibers (IENFs) in model mice. Macrophages infiltration were detected in DRG and sciatic nerve of model mice, which was reduced by EA. EA affected M1-like pro-inflammatory macrophage infiltration in DRG, whereas it did not affect M2-like macrophages. DRG neurons released chemoattractant CCL2 that recruited macrophages via CCR2 to DRG. EA reduced CCL2 overproduction by DRG neurons and reduced macrophage infiltration. Blocking CCR2 mimicked EA's anti-allodynic effect, whereas exogenously applying recombinant CCL2 reversed the ameliorative effect of EA on macrophage infiltration and abolished EA's anti-allodynia on model mice. EA ameliorated other signs of PIPN, including sensory neuron damage, sciatic nerve morphology impairment and IENFs loss. In mice inoculated with breast cancer cells, EA didn't affect paclitaxel-induced antitumor effect. Conclusions: These findings suggest EA alleviates PIPN by reducing CCL2/CCR2 mediated-pro-inflammatory macrophage infiltration into sensory ganglia as well as the sciatic nerve. Our study supports EA could be used as a potential non-pharmacological therapy for PIPN. [ABSTRACT FROM AUTHOR]

Neuropathic pain is the crucial dose-limiting side effect of paclitaxel in chemotherapy patients that negatively impacts the quality of life and survival. Currently, no effective treatment option is available. Aprepitant, a well-established chemotherapy antiemetic performing neurokinin-1 receptor antagonism, shows analgesic effects in some pain models. We studied aprepitant analgesic effects on the paclitaxel-induced neuropathic pain model in rats besides inflammatory markers assessment. Rats intraperitoneally received paclitaxel, reaching the cumulative paclitaxel dose of 8 mg/kg. Aprepitant was orally administered every alternate day between days 2 and 14, with a prescribed dosage of 10 or 20 mg/kg. The evaluation of mechanical allodynia and cold hyperalgesia involved the measurement of paw withdrawal threshold and acetone test score on days 0, 7, and 14. On day 14, paw licking latency was measured using a hot plate test before scarification and tissue collection for interleukin 1β, tumor necrosis factor α, and nuclear factor kappa B (NF-kB) evaluation. Paclitaxel induced neuropathy as indicated by a lowered hind paw withdrawal threshold in the Von Frey test, a higher score in the acetone test, and shortened hot plate latency. Aprepitant effectively alleviated cold and thermal hyperalgesia as well as mechanical allodynia. Moreover, aprepitant administration significantly reversed paclitaxel-mediated elevation of proinflammatory cytokines levels in dorsal root ganglia. In addition, aprepitant application suppressed the protein expression of NF-kB in the dorsal root ganglia of paclitaxel-treated rats, as revealed by western blot analysis. Aprepitant treatment ameliorates neuropathy induced by paclitaxel, which is associated with decreasing proinflammatory cytokines and NF-kB expression. [ABSTRACT FROM AUTHOR]

Peripheral Neuropathy (PN) can significantly impair quality of life, but often remains undiagnosed due to limited clinic time, lack of specialist expertise and lack of patient awareness. There are several validated questionnaires for diagnosing PN, but the time taken to administer them in busy primary care clinics limits their utilization. A new, simpler questionnaire was developed following an advisory board meeting in Southeast Asia and was further refined and translated to Portuguese and Spanish following a second advisory board meeting in Latin America. We consider current hurdles and propose a quick and reliable questionnaire that can be widely adopted to enable earlier diagnosis and improved management of PN in resource-limited settings in Latin America. [ABSTRACT FROM AUTHOR]

Transthyretin (TTR) amyloidosis is a progressive disorder characterized by peripheral neuropathy, autonomic dysfunction, and cardiomyopathy. The precise mechanism by which TTR misfolds and forms fibrils in vivo remains incompletely understood, posing challenges to the development of effective therapeutics. In this study, we reveal that the recently identified nonnative pathological species of TTR (NNTTR), which is enriched in the plasma of ttr-val30met gene carriers, exhibits strong amyloidogenic properties, making it a promising therapeutic target. Notably, we demonstrate that NNTTR formation is dependent on an intermolecular disulfide bond and can be promoted by oxidative conditions while being effectively suppressed by reducing agents. The formation of this disulfide bond is incompatible with the native TTR fold, thereby necessitating structural flexibility. We further show that this required flexibility can be constrained using tetramerstabilizing drugs, thereby suppressing NNTTR formation. Interestingly, the flexibility is also hindered by macromolecular crowding, and NNTTR formation is strongly suppressed by the high protein concentration in plasma. This suppression is released upon dilution, which thus promotes NNTTR formation in areas with lower protein content, highlighting a potential link to the interstitial space, brain, and vitreous body of the eye, where TTR-amyloid is frequently observed. In summary, we demonstrate that NNTTR displays strong amyloidogenic features, underscoring its potential as a therapeutic target. We identify the redox environment and macromolecular crowding as key modulatory factors. Our findings propose a mechanistic explanation for TTR misfolding and suggest a novel therapeutic approach. [ABSTRACT FROM AUTHOR]

Purpose: A comprehensive analysis of metabolites (metabolomics) has been proposed as a new strategy for analyzing liquid biopsies and has been applied to identify biomarkers predicting clinical responses or adverse events associated with specific treatments. Here, we aimed to identify metabolites associated with bortezomib (Btz)-related toxicities and response to treatment in newly diagnosed multiple myeloma (MM). Methods: Fifty-four plasma samples from transplant-ineligible MM patients enrolled in a randomized phase II study comparing two less-intensive regimens of melphalan, prednisolone and Btz (MPB) were subjected to the lipidomic profiling analysis. The amount of each lipid metabolite in plasma obtained prior to MPB therapy was compared to toxicity grades and responses to MPB therapy. Results: High levels of 7 phospholipids (4 lysophosphatidylcholines and 3 phosphatidylcholines) were observed in cases with Btz-induced ≥ grade 2 peripheral neuropathy (BiPN) (n = 11). In addition, low levels of 3 fatty acids (FAs)—FA (18:2), FA (18:1), and FA (22:6)—were observed in patients who developed severe skin disorders ≥ grade 2 (n = 10). No metabolite significantly associated with treatment response was identified. Conclusion: We conclude that levels of specific plasma lipid metabolites are associated with the severity of BiPN and skin disorders in patients with MM. These metabolites may serve as candidate biomarkers to predict Btz-induced toxicity in patients with MM before initiating Btz-containing therapy. [ABSTRACT FROM AUTHOR]

Background: Diabetic foot ulcers (DFU) are a common complication among diabetic patients, leading to an increased risk of amputation and mortality. About 15-25% of diabetics develop DFUs, with half of these cases requiring amputation. Early identification of high-risk patients, particularly those with peripheral neuropathy, is crucial in preventing DFUs. Non-invasive methods such as foot temperature monitoring and footprint analysis have shown promise in identifying these high-risk individuals. Aims and Objectives: This study aimed to evaluate the efficacy of foot temperature monitoring and footprint analysis in preventing DFUs in type 2 diabetic patients with peripheral neuropathy by identifying high-risk pressure points and temperature differences. Materials and Methods: A prospective study was conducted on 100 patients at Maharani Laxmi Bai Medical College, Jhansi, comprising 50 patients with diabetic neuropathy and foot ulcers and 50 patients with neuropathy but without ulcers. Foot temperature was monitored using a handheld infrared thermometer, while footprint analysis was conducted using a Harris mat. Patients were followed for 5 months to monitor the development of DFUs. Statistical analysis was performed using the Chi-square test, with a significance threshold of P<0.05. Results: Out of 50 neuropathic patients without ulcers, 14 (64%) developed DFUs, primarily in those with a foot temperature difference of >2°C and grade 3 or 4 pressure points. Foot temperature monitoring and footprint analysis showed a combined efficacy of 67% in predicting DFU development. The results were statistically significant (P<0.05). Conclusion: Foot temperature monitoring and footprint analysis are effective tools for predicting DFU development in diabetic neuropathy patients. Early identification of high-risk individuals allows for timely interventions, such as appropriate footwear, reducing DFU incidence and the associated risk of amputation. [ABSTRACT FROM AUTHOR]

New drug modalities offer life-saving benefits for patients through access to previously undruggable targets. Yet these modalities pose a challenge for the pharmaceutical industry, as side effects are complex, unpredictable, and often uniquely human. With animal studies having limited predictive value due to translatability challenges, the pharmaceutical industry seeks out new approach methodologies. Microphysiological systems (MPS) offer important features that enable complex toxicological processes to be modeled in vitro such as (a) an adjustable complexity of cellular components, including immune components; (b) a modifiable tissue architecture; (c) integration and monitoring of dynamic mechanisms; and (d) a multiorgan connection. Here we review MPS studies in the context of four clinical adverse events triggered by new drug modalities: peripheral neuropathy, thrombocytopenia, immune-mediated hepatotoxicity, and cytokine release syndrome. We conclude that while the use of MPS for testing new drug modality–induced toxicities is still in its infancy, we see strong potential going forward. [ABSTRACT FROM AUTHOR]

Background: Carpal tunnel syndrome (CTS) is a common peripheral neuropathy, often assessed using the Boston Carpal Tunnel Questionnaire (BCTQ). The BCTQ evaluates symptom severity (SSS) and functional status (FSS) but has limitations in stratifying CTS severity, particularly in severe cases. Objective: This study aimed to evaluate the utility of the BCTQ in a homogeneous cohort of female workers engaged in repetitive manual tasks, exploring its correlation with objective clinical measures and its performance in detecting CTS severity. Methods: A cross-sectional study was conducted on 24 right-hand-dominant female workers with repetitive occupational tasks. CTS diagnosis was confirmed via clinical and electrodiagnostic criteria. Subjects completed the BCTQ, and correlations between BCTQ scores and objective measures such as median nerve cross-sectional area and nerve conduction studies were analyzed. Statistical analyses included comparisons across CTS severity groups and subgroup evaluations based on age and tenure. Results: The BCTQ demonstrated moderate correlations with objective measures, with a strong correlation between SSS and FSS scores (r = 0.86, p < 0.001). However, the sensitivity of the SSS and FSS was limited, particularly for severe CTS cases. Paradoxically lower scores in severe cases may reflect questionnaire limitations or adaptive responses. Targeted questions addressing pain and sensory symptoms showed better sensitivity (>80%) and may guide clinicians in identifying slight CTS cases. Conclusions: While the BCTQ remains a valuable tool for assessing CTS, its limitations necessitate complementary use of objective diagnostic tools, particularly for severe cases. Future refinements, such as tailored scoring systems and integration with clinical measures, could enhance its diagnostic utility and ensure comprehensive assessment of CTS severity. [ABSTRACT FROM AUTHOR]