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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]

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: 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]

Background and Objectives: According to the International Working Group on Diabetic Foot (IWGDF) risk classification, the estimated risk of developing a diabetic foot ulcer (DFU) is much higher in patients with a history of DFUs (Grade 3) compared to those with a peripheral neuropathy but without a history of DFUs (Grades 1 and 2). It has been suggested that microcirculation impairment is involved in DFU genesis and could be taken into account to refine the existing risk classification. The aim of this study was to evaluate microcirculation parameters in patients with diabetes according to their estimated DFU risk. Materials and Methods: A total of 172 patients with type 2 diabetes associated with a peripheral neuropathy and/or a history of DFUs were included and classified into two groups (Grade 1–2 and Grade 3) according to the IWGDF classification. All patients underwent an evaluation of peripheral neuropathy, plantar sudomotor function, and skin microcirculation parameters. These different parameters were compared between both groups. Results: There was no significant difference between the two groups in terms of age, diabetes duration, transcutaneous oxygen pressure level, skin microcirculatory reactivity, neuropathy disability score, neuropathy symptom score, or thermal sensitivity. Patients in Grade 3 were more likely to present with retinopathy (OR 3.15, 95%CI [1.53; 6.49]) and severe sudomotor dysfunction (OR 2.73 95%CI [1.29; 5.80] but less likely to have abnormal VPT (OR 0.20 95%CI [0.05; 0.80]). Conclusions: The present study found more retinopathy and a more pronounced alteration to sudomotor function in Grade 3 patients, suggesting that these parameters could be considered to better identify patients at high risk of DFUs. [ABSTRACT FROM AUTHOR]

Background: Charcot–Marie–Tooth (CMT) disease is an inherited peripheral neuropathy primarily involving motor and sensory neurons. Mutations in INF2, an actin assembly factor, cause two diseases: peripheral neuropathy CMT-DIE (MIM614455) and/or focal segmental glomerulosclerosis (FSGS). These two phenotypes arise from the progressive degeneration affecting podocytes and Schwann cells. In general, nerve enlargement has been reported in 25% of the demyelinating CMT subtype (CMT1), while little is known about the CMT-DIE caused by INF2 variants. Methods: To characterize the peripheral nerve phenotype of INF2-related CMT, we studied the clinical course, imaging, histology, and germline genetic variants in two unrelated CMT-DIE patients. Results: Patient 1 (INF2 p.Gly73Asp) and patient 2 (p.Val108Asp) first noticed walking difficulties at 10 to 12 years old. Both of them were electrophysiologically diagnosed with demyelinating neuropathy. In patient 2, the sural nerve biopsy revealed an onion bulb formation. Both patients developed nephrotic syndrome almost simultaneously with CMT and progressed into renal failure at the age of 16 to 17 years. Around the age of 30 years, both patients manifested multiple hypertrophy of the trunk, plexus, and root in the cervical, brachial, lumbosacral nerves, and cauda equina. The histology of the cervical mass in patient 2 revealed Schwannoma. Exome analysis showed that patient 2 harbors a germline LZTR1 p.Arg68Gly variant, while patient 1 has no schwannomatosis-related mutations. Conclusions: Peripheral neuropathy caused by INF2 variants may lead to the development of multifocal hypertrophy with age, likely due to the initial demyelination and subsequent Schwann cell proliferation. Schwannoma could co-occur when the tissues attain additional hits in schwannomatosis-related genes (e.g., LZTR1). [ABSTRACT FROM AUTHOR]

Simple Summary: Chemotherapy-induced neuropathy is a major clinical problem, with limited treatments available to try to reverse it. Some preliminary data suggested that palmitoylethanolamide (PEA) may effectively treat this condition. Pursuant to this, a placebo-controlled, double-blind, randomized phase 2 clinical trial was developed to look for evidence to support a future, more definitive phase 3 clinical trial. Eighty-nine patients participated in this clinical trial. Unfortunately, the data from the present phase 2 trial did not support the idea that PEA was useful in this situation. Background: Chemotherapy-induced peripheral neuropathy (CIPN) from oxaliplatin and taxane drugs is a bothersome toxicity. Palmitoylethanolamide (PEA) has been reported to improve myelinated nerve fiber function in patients experiencing painful CIPN. We conducted a double-blind, placebo-controlled, randomized trial of PEA in patients with established CIPN. Methods: Eligible patients were adults who had pain, numbness, tingling, or other symptoms of CIPN for at least three months following completion of paclitaxel, oxaliplatin, or cisplatin-based chemotherapy. Study patients were randomized to one of the two treatment groups (PEA versus placebo, both administered either once or twice daily). The CIPN20 questionnaire was assessed weekly. Results: A total of 17 males and 71 females participated in the study; most had neuropathy from paclitaxel. Most (85%) finished 8 weeks of treatment. There was no suggestion that either of the PEA arms did any better than the combined placebo arms. There was no signal of significant toxicity differences between the three study arms. Quality of life outcome measures were similar between the study arms, as were cognitive function evaluations. Discussion: PEA failed to improve established CIPN. Future trials might explore whether PEA may be effective in preventing CIPN or cognitive changes based on data that suggest it may be helpful in this situation. Conclusions: PEA failed to improve established chemotherapy-induced neuropathy. [ABSTRACT FROM AUTHOR]

Objectives: Neurotoxic effects causing peripheral nerve damage have been reported for several chemotherapy agents. There is no established and standardized method to assess the presence of chemotherapy-induced peripheral neuropathy (CIPN). We compared patient-reported CIPN symptoms to neurophysiological findings and neurological assessments in patients receiving taxane-based chemotherapy. Methods: Patients scheduled to receive taxane-based chemotherapy for the treatment of gynecologic cancer were included and prospectively followed for up to 9 months after chemotherapy discontinuation, between May 2020 and January 2023. Patient-reported symptoms, using the EORTC-QLQ-CIPN20 questionnaire, and nerve conduction studies (NCSs) were performed at baseline, halfway through the treatment cycle, at the end of the treatment, 3 months after treatment, and 6–9 months after treatment. Results: A total of 149 patients were included. Overall, 47.0% of patients reported symptoms compatible with CIPN at any of the follow-ups. Subjective symptoms did not correlate with nerve conduction studies. SNAP amplitudes at baseline were lower in patients who developed CIPN compared to the group without CIPN. Conclusions: The overall diagnostic accuracy of electrophysiological parameters as a marker for CIPN was low. [ABSTRACT FROM AUTHOR]

Background/Objectives: Axonal Charcot–Marie–Tooth disease type 2 (CMT2) accounts for 24% of Hereditary Motor/Sensory Peripheral Neuropathies. CMT2 type GG, due to four distinct heterozygous mutations in the Golgi brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1) gene (OMIM 606483), was described in seven cases from four unrelated families with autosomal dominant inheritance. It is characterized by slowly progressive distal muscle weakness and atrophy, primarily affecting the lower limbs. Here, we present two siblings sharing a novel GBF1 variant. Methods: Patient II.1 (male, 61 years at onset) presented lower limb hypoesthesia and walking difficulty; the examination revealed a postural tremor, a positive Romberg test, and muscle atrophy in the lower limbs and hands. Patient II.2 (his sister, 59 years at onset) had lower limb dysesthesias, hand paresthesia, and lower-limb stiffness. They underwent clinical evaluations, blood tests, and electroneurography. Their father represents a potentially affected individual, although a genetic analysis was not conducted. Results: All tests for peripheral neuropathies were unremarkable, including metabolic and autoimmune screening. Both showed a mixed demyelinating–axonal sensory–motor neuropathy. Genetic analysis revealed a new heterozygous GBF1 variant of uncertain significance. Conclusions: Based on autosomal dominant inheritance, as well as clinical and physiological features, a possible novel CMT2GG was diagnosed. Further research, including functional assays and in vitro studies, is necessary to confirm this variant's causal link. [ABSTRACT FROM AUTHOR]

Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of highly active antiretroviral therapy (HAART)—the current standard of care for treating human immunodeficiency virus (HIV) infection. Despite their efficacy, NRTIs cause numerous treatment-limiting adverse effects, including a distinct peripheral neuropathy, called antiretroviral toxic neuropathy (ATN). ATN primarily affects the extremities with shock-like tingling pain, a pins-and-needles prickling sensation, and numbness. Despite its negative impact on patient quality of life, ATN remains poorly understood, which limits treatment options and potential interventions for people living with HIV (PLWH). Elucidating the underlying pathophysiology of NRTI-induced ATN will facilitate the development of effective treatment strategies and improved patient outcomes. In this article, we will comprehensively review ATN in the setting of NRTI treatment for HIV infection. [ABSTRACT FROM AUTHOR]

Although the literature on patient-reported outcomes (PROMs) continues to expand, challenges persist in selecting reliable and valid instruments for assessing peripheral neuropathy (PN) in patients with cancer. This systematic review aimed to identify all validated self-report PN scales and critically appraise their measurement properties. This review was conducted using the COSMIN methodology for PROMs and the PRISMA statement. Five databases were searched from inception to August 2024, identifying 46 eligible studies and 16 PROMs. Evidence quality ranged from "very low" to "moderate", with notable inconsistencies in the content and structural validity phases of most instruments. Instruments such as the Chemotherapy-induced peripheral neuropathy assessment tool and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity demonstrated moderate quality and potential utility in clinical practice, while others, including the Location-based assessment of sensory symptoms in cancer and the Measure of Ovarian Symptoms and Treatment, had insufficient evidence to support their use. Importantly, all PROMs focused on chemotherapy-induced peripheral neuropathy, highlighting a significant gap in instruments addressing other PN causes, such as radiotherapy or tumor-related nerve damage. Further research should prioritize developing and validating instruments for distinct cancer populations, ensuring robust psychometric properties and clinical applicability. [ABSTRACT FROM AUTHOR]

Background/Objectives: This paper proposes a method for managing gait imbalances by integrating the Internet of Things (IoT) and machine learning technologies. Ankle–foot orthosis (AFO) devices are crucial medical braces that align the lower leg, ankle, and foot, offering essential support for individuals with gait imbalances by assisting weak or paralyzed muscles. This research aims to revolutionize medical orthotics through IoT and machine learning, providing a sophisticated solution for managing gait issues and enhancing patient care with personalized, data-driven insights. Methods: The smart ankle–foot orthosis (AFO) is equipped with a surface electromyography (sEMG) sensor to measure muscle activity and an Inertial Measurement Unit (IMU) sensor to monitor gait movements. Data from these sensors are transmitted to the cloud via fog computing for analysis, aiming to identify distinct walking phases, whether normal or aberrant. This involves preprocessing the data and analyzing it using various machine learning methods, such as Random Forest, Decision Tree, Support Vector Machine (SVM), Artificial Neural Network (ANN), Long Short-Term Memory (LSTM), and Transformer models. Results: The Transformer model demonstrates exceptional performance in classifying walking phases based on sensor data, achieving an accuracy of 98.97%. With this preprocessed data, the model can accurately predict and measure improvements in patients' walking patterns, highlighting its effectiveness in distinguishing between normal and aberrant phases during gait analysis. Conclusions: These predictive capabilities enable tailored recommendations regarding the duration and intensity of ankle–foot orthosis (AFO) usage based on individual recovery needs. The analysis results are sent to the physician's device for validation and regular monitoring. Upon approval, the comprehensive report is made accessible to the patient, ensuring continuous progress tracking and timely adjustments to the treatment plan. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgical treatment of rectal cancer with a low anterior resection allows patients to maintain normal anatomy. Despite this, many patients can postoperatively develop symptoms related to bowel dysfunction known as low anterior resection syndrome (LARS). Systemic therapy for rectal cancer treatment often includes platinum-based chemotherapy agents with peripheral neuropathy as a common side effect. LARS and chemotherapy-induced peripheral neuropathy (CIPN) may greatly affect a patient's quality of life. Thus, the purpose of this study was to evaluate a potential relationship between CIPN and LARS. We found there was an association between CIPN and the development of LARS. Thus, further studies should look to evaluate the possible biological mechanisms behind this relationship. Introduction: Low anterior resection syndrome (LARS) can be a debilitating condition that develops after undergoing sphincter-preserving surgery for rectal cancer. Chemotherapy-induced peripheral neuropathy is a common side effect of platinum-based chemotherapy agents used as systemic therapy for rectal cancer treatment. The purpose of this study was to determine the potential relationship between CIPN and LARS. Methods: This was a retrospective review of patients who underwent a low anterior resection for rectal cancer and received systemic therapy contacted at least six months from the most recent surgery. Eligible patients were called and completed the relevant surveys over the phone or email. Results: There was a total of 42 patients who completed the surveys with 33 (79%) having major LARS. Presence of a diverting ileostomy was the only significantly differentcharacteristic in those with major LARS versus those without. CIPN was independently associated with LARS (p = 0.046) on linear regression when controlling for neoadjuvant chemoradiation, diverting ileostomy and tumor distance from the anal verge. Conclusions: Developing severe CIPN is associated with developing LARS. Further studies evaluating the etiology behind this relationship should be conducted. [ABSTRACT FROM AUTHOR]

Background/Objectives: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) that combines monomethyl auristatin E (MMAE), a potent cytotoxic agent, with a monoclonal antibody targeting Nectin-4. It has emerged as a promising therapy for metastatic urothelial carcinoma (mUC), either as monotherapy or in combination with pembrolizumab, improving significantly the overall survival of these patients. EV is associated with common adverse events, including skin reactions, glucose imbalance, and peripheral neuropathy, which are usually mild in severity and easily manageable. Methods: Following an initial case of pleuro-pneumopathy occurring in a patient treated with EV, we conducted a retrospective analysis of EV effects on pulmonary imaging. Results: In a cohort of 20 all-comers mUC patients, we identified three cases of potentially EV-related lung toxicity, resulting in a pleuro-pneumopathy rate of 15%. Two of these cases appeared highly symptomatic and required high steroid doses, with a rapid resolution of symptoms and normalization of radiological findings. In one patient, rechallenge of EV was associated with reoccurrence of pneumopathy. We described the clinical and radiological features of these cases, as well as their evolution after EV discontinuation and rechallenge. Conclusions: This case series underscores the importance of close pulmonary monitoring during EV treatment. [ABSTRACT FROM AUTHOR]

Background/Objectives: To address the unmet clinical needs in the treatment of epilepsy and pain, the continued development of more effective and safer anticonvulsants and analgesics is still necessary. Therefore, herein we report synthesis and antiseizure/antinociceptive evaluation of a focused series of 3-(benzo[b]thiophen-2-yl)pyrrolidine-2,5-dione derivatives. Methods: The anticonvulsant properties were investigated in acute models of seizures, namely the maximal electroshock (MES), the 6 Hz (32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas analgesic activity was tested in the model of a tonic pain/formalin test and oxaliplatin-induced neuropathic pain (in CD-1-mice, i.p.). In addition, a number of in vitro assays were performed, aiming at the evaluation of the drug-like properties of the compounds disclosed herein. Results: We identified 33 as a lead compound with the most promising antiseizure properties, i.e., ED50 (MES) = 27.4 mg/kg and ED50 (6 Hz, 32 mA) = 30.8 mg/kg. Furthermore, 33 at a dose of 100 mg/kg significantly prolonged the latency time to the first seizure episode in the scPTZ model and at high doses did not impaire coordination of mice in the rotarod test (TD50 > 200 mg/kg). Apart from broad antiseizure protection, 33 demonstrated a significant analgesic effect in the formalin test (45 mg/kg, i.p.), and effectively alleviated allodynia in the oxaliplatin-induced neuropathic pain model (30 and 45 mg/kg). The binding assays suggest that the most plausible mechanism of action relies on interaction with the neuronal voltage-sensitive sodium channel (site 2). Furthermore, the drug-like potential of 33 supports favorable in vitro results, i.e., no hepatocytotoxicity and neurocytotoxicity at a high concentration of 100 μM, as well as a lack of mutagenicity at a concentration as high as 500 μM. Conclusions: Compound 33 identified in the current studies is proposed to be an interesting candidate for further preclinical development as therapy for epilepsy and neuropathic pain. [ABSTRACT FROM AUTHOR]

The eye, and the cornea in particular, is a common site of chemotherapy induced toxicity, and ocular side effects of both traditional and novel agents have been reported. Corneal confocal microscopy (CCM) is an in vivo technique that allows for the study of all the corneal layers in an easy, non-invasive and reproducible way via the direct visualization of corneal cell morphologies as well as of sub-basal nerve plexus. Thus, it represents a useful way to identify and monitor chemotherapy induced corneal alterations. This work aims to review the use of CCM in identifying corneal toxicity secondary to chemotherapy treatment, as regards both corneal nerves alterations in the setting of chemotherapy induced peripheral neuropathy (CIPN) and other corneal structure changes, particularly involving the corneal epithelium. [ABSTRACT FROM AUTHOR]

A microphysiological system (MPS) is an in vitro culture technology that reproduces the physiological microenvironment and functionality of humans and is expected to be applied for drug screening. In this study, we developed an MPS for the structured culture of human iPSC-derived sensory neurons and then predicted drug-induced neurotoxicity by morphological deep learning. Using human iPSC-derived sensory neurons, after the administration of representative anti-cancer drugs, the toxic effects on soma and axons were evaluated by an AI model with neurite images. Significant toxicity was detected in positive drugs and could be classified by different effects on soma or axons, suggesting that the current method provides an effective evaluation of chemotherapy-induced peripheral neuropathy. The results of neurofilament light chain expression changes in the MPS device also agreed with clinical reports. Therefore, the present MPS combined with morphological deep learning is a useful platform for in vitro peripheral neurotoxicity assessment. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2DM) affects over 500 million people worldwide, and over 50% of this group experience the most common complication, diabetic peripheral neuropathy (DPN). The presence of advanced glycation end-products (AGEs) has been linked with the development of DPN. The present study assessed AGE levels in participants with type 2 diabetes and explored the hypothesis that there may be increased AGE levels in more severe DPN. Methods: A total of 124 participants with T2DM were consecutively recruited, and they underwent skin autofluorescence, clinical assessment for peripheral neuropathy, peripheral nerve ultrasound, nerve conduction studies, and axonal excitability assessment. Results: AGE accumulation showed weak but significant correlations with neuropathy severity and reduced nerve conduction function. However, after adjusting for confounding variables, a linear regression analysis did not reveal significant associations between the AGE levels and neuropathy outcomes. Conclusions: The present study suggests that the accumulation of AGE is not associated with the clinical, electrophysiological, and morphological measures of neuropathy in T2DM. [ABSTRACT FROM AUTHOR]

The sural nerve provides sensory innervation to the skin on the distal posterolateral third of the lower extremity. The morphological variants are characterized by high variability. However, it most commonly arises from a union of the medial sural cutaneous nerve and the peroneal communicating branch of the common fibular nerve. This article overviews the anatomical and clinical significance of the sural nerve. Despite the remarkable development of genetic diagnostics, sural nerve biopsy is still a very important tool to diagnose peripheral neuropathies such as diabetic, vascular and inflammatory neuropathies. Furthermore, the sural nerve is also commonly transplanted due to its characteristics. Such a procedure is applicable in cases of segmental nerve loss, but it is also used to restore potency in patients after radical prostatectomy. The knowledge of anatomical variants of the sural nerve is also crucial as it allows to minimize its damage during surgical procedures. Furthermore, during an ankle surgery, a nerve block can be used to complement anesthesia. The major aim of this work is to review contributions of the sural nerve to physiological and pathophysiological processes. [ABSTRACT FROM AUTHOR]

Background: Tug-of-War (TOW) games involve repetitive hand movements and vigorous force, raising the risk of peripheral neuropathy in the upper extremities. The prevalence of carpal tunnel syndrome (CTS) in TOW athletes remains unclear. We hypothesize that elite female TOW athletes have a higher prevalence of CTS than the general population. Methods: Twenty-nine female TOW athletes were recruited from a national team and participated in the study. CTS was clinically diagnosed by history taking and physical examination. Nerve conduction studies (NCS) were additionally performed to confirm CTS. Results: Twelve athletes were clinically diagnosed with CTS; however, only nine were confirmed by NCS. Ten athletes were diagnosed with subclinical CTS by NCS, while seven were classified as truly-non-CTS by both clinical assessment and NCS. The prevalence of CTS and subclinical CTS among the athletes was found to be 33.3% and 37.0%, respectively, significantly higher than 2.7% in the general population by electrodiagnosis. The body weight (p = 0.025) of the athletes with CTS and subclinical CTS was significantly different from those of the athletes without CTS. Conclusions: Our observations revealed a higher prevalence of CTS among elite female TOW athletes, with body weight being a risk factor. The forceful grasping and pulling of the rope may contribute to the development of CTS. [ABSTRACT FROM AUTHOR]

The cytoskeleton mediates fundamental cellular processes by organizing inter-organelle interactions. Pathogenic variants of inverted formin 2 (INF2) CAAX isoform, an actin assembly factor that is predominantly expressed in the endoplasmic reticulum (ER), are linked to focal segmental glomerulosclerosis (FSGS) and Charcot–Marie–Tooth (CMT) neuropathy. To investigate how pathogenic INF2 variants alter ER integrity, we used high-resolution live imaging of HeLa cells. Cells expressing wild-type (WT) INF2 showed a predominant tubular ER with perinuclear clustering. Cells expressing INF2 FSGS variants that cause mild and intermediate disease induced more sheet-like ER, a pattern similar to that seen for cells expressing WT-INF2 that were treated with actin and microtubule (MT) inhibitors. Dual CMT-FSGS INF2 variants led to more severe ER dysmorphism, with a diffuse, fragmented ER and coarse INF2 aggregates. Proper organization of both F-actin and MT was needed to modulate the tubule vs. sheet conformation balance, while MT arrays regulated spatial expansion of tubular ER in the cell periphery. Pathogenic INF2 variants also induced mitochondria fragmentation and dysregulated mitochondria distribution. Such mitochondrial abnormalities were more prominent for cells expressing CMT-FSGS compared to those with FSGS variants, indicating that the severity of the dysfunction is linked to the degree of cytoskeletal disorganization. Our observations suggest that pathogenic INF2 variants disrupt ER continuity by altering interactions between the ER and the cytoskeleton that in turn impairs inter-organelle communication, especially at ER–mitochondria contact sites. ER continuity defects may be a common disease mechanism involved in both peripheral neuropathy and glomerulopathy. [ABSTRACT FROM AUTHOR]

Meralgia paresthetica is a compressive neuropathy of the lateral femoral cutaneous nerve. Surgery is the gold standard for severe cases. However, no high-quality evidence exists on which strategy is best: decompression or neurectomy. Data of a consecutive series of 52 patients treated for meralgia paresthetica over 25 years (1997–2022) were retrospectively collected from medical records and telephone interviews. In total, 27 women and 25 men were operated on; 11 patients had iatrogenic meralgia paresthetica. Decompression was performed on 47 patients, and neurectomy in 8 cases (5 primary neurectomies plus 3 failed neurolysis). Out of the patients who underwent decompression, 41 (87.2%) benefited from the treatment; 3 had pain relief, but no benefit on paresthesia; and 3 reported pain persistence. The latter required neurectomy to resolve symptoms. The eight patients who underwent neurectomy experienced symptom relief but had an obvious anesthetic area persisting over years. Complications were rare (3.8%): a groin hematoma in the post-operative course and an inguinal herniation 6 months after surgery. Surgery, be it neurolysis or neurectomy, offers excellent results with low risks. Decompression has been proven to be adequate in almost all patients, avoiding the side effects of neurectomy. The latter should be confined to failed decompression or to iatrogenic meralgia. [ABSTRACT FROM AUTHOR]

Pressure-relieving footwear helps prevent foot ulcers in people with diabetes. The footwear design contributes to this effect and includes the insole top cover. We aimed to assess the offloading effect of materials commonly used as insole top cover. We measured 20 participants with diabetes and peripheral neuropathy for in-shoe peak pressures while walking in their prescribed footwear with the insole covered with eight different materials, tested in randomized order. Top covers were a 3 mm or 6 mm thick open or closed-cell foam or a 6 mm thick combination of open- and closed-cell foams. We re-assessed pressures after one month of using the top cover. Peak pressures were assessed per anatomical foot region and a region of interest (i.e., previous ulceration or high barefoot pressure). Walking comfort was assessed using a 10-point Likert scale. Mean peak pressure at the region of interest varied between 167 (SD:56) and 186 (SD:65) kPa across top covers (p < 0.001) and was significantly higher for the 3 mm thick PPT than for four of the seven 6 mm thick top covers. Across 6 mm thick top covers, only two showed a significant peak pressure difference between them. Over time, peak pressures changed non-significantly from −2.7 to +47.8 kPa across top cover conditions. Comfort ratings were 8.0 to 8.4 across top covers (p = 0.863). The 6 mm thick foams provided more pressure relief than the 3 mm thick foam during walking in high-risk people with diabetes. Between the 6 mm thick foams and over time, only small differences exist. The choice of which 6 mm thick insole top cover to use may be determined more by availability, durability, ease of use, costs, or hygienic properties than by superiority in pressure-relief capacity. [ABSTRACT FROM AUTHOR]

Background: Sterile α and Toll/IL-1 receptor motif-containing 1 (SARM1) is a central regulator of programmed axon death and a crucial nicotinamide adenine dinucleotide (NAD+) hydrolase (NADase) in mammalian tissues, hydrolyzing NAD+ and playing an important role in cellular NAD+ recycling. Abnormal SARM1 expression is linked to axon degeneration, which causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Methods: In this study, we use PC6 assay of hydrolase activity, DRG axon regeneration and CIPN model to screen for potent SARM1 Inhibitors. Results: Two novel SARM1 inhibitors (compound 174 and 331P1) are charcterized for its high potency for SARM1 NADase. In a chemotherapy-induced peripheral neuropathy (CIPN) myopathy model, compound 331P1 treatment prevented the decline in neurofilament light chain (NfL) levels caused by axonal injury in a dose-dependent manner, associated with elevated intraepidermal nerve fiber (IENF) intensity in mouse foot paw tissue, suggesting its functionality in reversing axon degeneration. Conclusions: The newly designed SARM1 inhibitor 331P1 is a promising candidate due to its excellent in vivo efficacy, favorable CYP inhibition properties, and attractive safety profiles. The 331P1 compound possesses the potential to be developed as a novel neuroprotective therapy that can prevent or halt the neurodegenerative process in CIPN. [ABSTRACT FROM AUTHOR]

Charcot–Marie–Tooth neuropathy type 4D (CMT4D) is a rare genetic disorder of the peripheral nervous system caused by biallelic mutations in the N-Myc Downstream Regulated 1 gene (NDRG1). Patients present with an early onset demyelinating peripheral neuropathy causing severe distal muscle weakness and sensory loss, leading to loss of ambulation and progressive sensorineural hearing loss. The disorder was initially described in the Roma community due to a common founder mutation, and only a handful of disease-causing variants have been described in this gene so far. Here, we present genetic and clinical findings from a large Bulgarian cohort of demyelinating CMT patients harboring recurrent and novel variants in the NDRG1 gene. Notably, two splice-site variants are exclusive to Bulgarian Muslims and reside in ancestral haplotypes, suggesting a founder effect. Functional characterization of these novel variants implicates a loss-of-function mechanism due to shorter gene products. Our findings contribute to a deeper understanding of the genetic and clinical heterogeneity of CMT4D and highlight novel founder mutations in the ethnic minority of Bulgarian Muslims. [ABSTRACT FROM AUTHOR]

Cancer is the leading cause of disease-related death among children. Vincristine (VCR), a key component of childhood cancer treatment protocols, is associated with the risk of peripheral neuropathy (PN), a condition that may be reversible upon drug discontinuation but can also leave lasting sequelae. Single nucleotide polymorphism (SNP) in genes involved in VCR pharmacokinetics and pharmacodynamics have been investigated in relation to an increased risk of PN. However, the results of these studies have been inconsistent. A retrospective cohort study was conducted to investigate the potential association of drug transporter genes from the ATP-binding cassette (ABC) family and the centrosomal protein 72 (CEP72) gene with the development of PN in 88 Caucasian children diagnosed with cancer and treated with VCR. Genotyping was performed using real-time PCR techniques for the following SNPs: ABCB1 rs1128503, ABCC1 rs246240, ABCC2 rs717620, and CEP72 rs924607. The results indicated that age at diagnosis (OR = 1.33; 95% CI = 1.07–1.75) and the ABCC1 rs246240 G allele (OR = 12.48; 95% CI = 2.26–100.42) were associated with vincristine-induced peripheral neuropathy (VIPN). No association was found between this toxicity and CEP72 rs924607. Our study provides insights that may contribute to optimizing childhood cancer therapy in the future by predicting the risk of VIPN [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a major long-lasting side effect of some chemotherapy drugs, which threatens cancer survival rate. CIPN mostly affects sensory neurons and occasionally motor neurons, causing numbness, tingling, discomfort, and burning pain in the upper and lower extremities. The pathophysiology of CIPN is not completely understood; however, it is believed that chemotherapies induce peripheral neuropathy via directly damaging mitochondria, impairing the function of ion channels, triggering immunological mechanisms, and disrupting microtubules. The treatment of CIPN is a medical challenge, and there are no approved pharmacological options. Currently, duloxetine and other antidepressants, antioxidant, anti-inflammatory, and ion-channel targeted therapies are commonly used in clinics to relieve the symptoms of CIPN. Several other types of drugs, such as cannabinoids, sigma−1 receptor antagonists, and nicotinamides ribose, are being evaluated in preclinical and clinical studies. This paper summarizes the information related to the physiology of CIPN and medicines that could be used for treating this condition. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy (PN) is a multifaceted disorder characterised by peripheral nerve damage, manifesting in symptoms like pain, weakness, and autonomic dysfunction. This review assesses preclinical models in PN research, evaluating their relevance to human disease and their role in therapeutic development. The Streptozotocin (STZ)-induced diabetic rat model is widely used to simulate diabetic neuropathy but has limitations in faithfully replicating disease onset and progression. Cisplatin-induced PN models are suitable for studying chemotherapy-induced peripheral neuropathy (CIPN) and closely resemble human pathology. However, they may not fully replicate the spectrum of sensory and motor deficits. Paclitaxel-induced models also contribute to understanding CIPN mechanisms and testing neuroprotective agents. Surgical or trauma-induced models offer insights into nerve regeneration and repair strategies. Medications such as gabapentin, pregabalin, duloxetine, and fluoxetine have demonstrated promise in these models, enhancing our understanding of their therapeutic efficacy. Despite progress, developing models that accurately mirror human PN remains imperative due to its complex nature. Continuous refinement and innovative approaches are critical for effective drug discovery. This review underscores the strengths and limitations of current models and advocates for an integrated approach to address the complexities of PN better and optimise treatment outcomes. [ABSTRACT FROM AUTHOR]

The prevalence of N. medianus compression neuropathies remains high in clinical practice. The objective was to evaluate modalities of conservative treatments for carpal tunnel syndrome (CTS) focusing on the role of acetylcholinesterase inhibitors. This observational study involved 51 adult outpatients diagnosed with CTS. Patients were observed during routine clinical protocols and we compared two groups of 25 and 26 individuals, with the first group receiving basic therapy for CTS and 20 mg of ipidacrine (Neiromidin®) two or three times a day per os, while the second group received only basic therapy. The condition of all patients was assessed twice, with at least a one-month interval. The parameters evaluated included the Boston Carpal Tunnel Questionnaire (BCTQ); the Disabilities of the Arm, Shoulder, and Hand scale (DASH); and pain intensity on the Numeric Rating Scale (NRS). The mean reduction in DASH score was 12.3 (SD 7.7) in Group 1 and 7.1 (SD 6.3) in Group 2 (p < 0.01). Also, other scores showed statistically significant differences between the two groups: −2.3 vs. −1.0 for NRS, −0.89 vs. −0.44 for SSS, and −0.68 vs. −0.31 for FSS, respectively (p < 0.01). Moreover, these findings correlated positively with the global improvement (CGI-I) between the groups. The addition of ipidacrine to basic therapy led to improved recovery in patients with CTSs of varying severity. [ABSTRACT FROM AUTHOR]

Simple Summary: This article outlines a framework for the development and maintenance of chemotherapy-induced peripheral neuropathy using the 3P model, which focuses on predisposing, precipitating, and perpetuating factors. Predisposing factors increase the risk of CIPN onset; chemotherapy triggers the development of CIPN; and perpetuating factors maintain CIPN and limit recovery, such that CIPN becomes a chronic condition. In our proposed model, we have identified demographic, genetic, and clinical factors, such as comorbidities, as predisposing factors. Chemotherapy type, dose, and schedule are precipitating factors. Perpetuating factors include depression and physical activity. The proposed model can be used to identify treatment targets for the management of chemotherapy-induced peripheral neuropathy. Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating symptom experienced by cancer survivors. Despite the burden of CIPN-related symptoms, interventions remain limited. Objectives: This narrative review seeks to propose a framework for CIPN predisposing, precipitating, and perpetuating factors (3Ps), which will provide a foundation for future research and clinical interventions aimed at mitigating CIPN-related symptoms and morbidity. Methods: A comprehensive literature search was performed using PubMed, guided by keywords related to "chemotherapy-induced peripheral neuropathy." Studies were limited to those with full text available in English. Results: Predisposing factors outlined in this framework, such as older age and comorbid conditions, can be used to identify patients who have a higher risk of developing CIPN. The major precipitating factor of CIPN is the delivery of chemotherapy to peripheral nerves, which may be mitigated via cryotherapy or compression therapy during chemotherapy. Perpetuating factors can offer insight into psychological, cognitive, and behavioral modifications that could be treatment targets for CIPN management. Conclusion: The proposed 3P model can guide the development of effective interventions for CIPN by suggesting modifiable psychological and behavioral treatment targets that may mitigate the impact of CIPN for cancer patients. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect of cancer treatment, often linked with pain complaints. Patients report mechanical and thermal hypersensitivity that may emerge during chemotherapy treatment and may persist after cancer remission. Whereas the latter situation disturbs the quality of life, life itself may be endangered by the appearance of CIPN during cancer treatment. The causes of CIPN have almost entirely been ascribed to the neurotoxicity of chemotherapeutic drugs in the peripheral nervous system. However, the central consequences of peripheral neuropathy are starting to be unraveled, namely in the supraspinal pain modulatory system. Based on our interests and experience in the field, we undertook a review of the brain-centered alterations that may underpin pain in CIPN. The changes in the descending pain modulation in CIPN models along with the functional and connectivity abnormalities in the brain of CIPN patients are analyzed. A translational analysis of preclinical findings about descending pain regulation during CIPN is reviewed considering the main neurochemical systems (serotoninergic and noradrenergic) targeted in CIPN management in patients, namely by antidepressants. In conclusion, this review highlights the importance of studying supraspinal areas involved in descending pain modulation to understand the pathophysiology of CIPN, which will probably allow a more personalized and effective CIPN treatment in the future. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) remains a clinical challenge for up to 80% of breast cancer survivors. In an open-label study, participants underwent three interventions: standard care (duloxetine) for 1 month (Phase 1), oral cannabidiol (CBD) for 2 months (Phase 2), and CBD plus multi-modal exercise (MME) for another 2 months (Phase 3). Clinical outcomes and gut microbiota composition were assessed at baseline and after each phase. We present the case of a 52-year-old female with a history of triple-negative breast cancer in remission for over five years presenting with CIPN. She showed decreased monocyte counts, c-reactive protein, and systemic inflammatory index after each phase. Duloxetine provided moderate benefits and intolerable side effects (hyperhidrosis). She experienced the best improvement and least side effects with the combined (CBD plus MME) phase. Noteworthy were clinically meaningful improvements in CIPN symptoms, quality of life (QoL), and perceived physical function, as well as improvements in pain, mobility, hand/finger dexterity, and upper and lower body strength. CBD and MME altered gut microbiota, showing enrichment of genera that produce short-chain fatty acids. CBD and MME may improve CIPN symptoms, QoL, and physical function through anti-inflammatory and neuroprotective effects in cancer survivors suffering from long-standing CIPN. [ABSTRACT FROM AUTHOR]

Chemotherapy-provoked peripheral neuropathy and its associated affective disorders are important adverse effects in cancer patients, and its treatment is not completely resolved. A recent study reveals a positive interaction between molecular hydrogen (H2) and a heme oxygenase (HO-1) enzyme inducer, cobalt protoporphyrin IX (CoPP), in the inhibition of neuropathic pain provoked by nerve injury. Nevertheless, the efficacy of CoPP co-administered with hydrogen-rich water (HRW) on the allodynia and emotional disorders related to paclitaxel (PTX) administration has not yet been assessed. Using male C57BL/6 mice injected with PTX, we examined the effects of the co-administration of low doses of CoPP and HRW on mechanical and thermal allodynia and anxiodepressive-like behaviors triggered by PTX. Moreover, the impact of this combined treatment on the oxidative stress and inflammation caused by PTX in the amygdala (AMG) and dorsal root ganglia (DRG) were studied. Our results indicated that the antiallodynic actions of the co-administration of CoPP plus HRW are more rapid and higher than those given by each of them when independently administered. This combination inhibited anxiodepressive-like behaviors, the up-regulation of the inflammasome NLRP3 and 4-hydroxynonenal, as well as the high mRNA levels of some inflammatory mediators. This combination also increased the expression of NRF2, HO-1, superoxide dismutase 1, glutathione S-transferase mu 1, and/or the glutamate-cysteine ligase modifier subunit and decreased the protein levels of BACH1 in the DRG and/or AMG. Thus, it shows a positive interaction among HO-1 and H2 systems in controlling PTX-induced neuropathy by modulating inflammation and activating the antioxidant system. This study recommends the co-administration of CoPP plus HRW as an effective treatment for PTX-provoked neuropathy and its linked emotive deficits. [ABSTRACT FROM AUTHOR]

Traumatic peripheral nerve injuries (PNI), present with symptoms ranging from pain to loss of motor and sensory function. Difficulties in intraoperative visual assessment of nerve functional status necessitate intraoperative nerve conduction studies (INCSs) by neurosurgeons and neurologists to determine the presence of functioning axons in the zone of a PNI. This process, also referred to as nerve "inching", uses a set of stimulating and recording electrode hooks to lift the injured nerve from the surrounding surgical field and to determine whether an electrical stimulus can travel through the zone of injury. However, confounding electrical signal artifacts can arise from the current workflow and electrode design, particularly from the mandatory lifting of the nerve, complicating the definitive assessment of nerve function and neurosurgical treatment decision-making. The objective of this study is to describe the design process and verification testing of our group's newly designed stimulating and recording electrodes that do not require the lifting or displacement of the injured nerve during INCSs. Ergonomic in vivo analysis of the device within a porcine model demonstrated successful intraoperative manipulation of the device, while quantitative nerve action potential (NAP) signal analysis with an ex vivo simulated "inching" procedure on healthy non-human primate nerve tissue demonstrated excellent reproducible recorded NAP fidelity and the absence of NAP signal artifacts at all points of recording. Lastly, electrode pullout force testing determined maximum forces of 0.43 N, 1.57 N, and 3.61 N required to remove the device from 2 mm, 5 mm, and 1 cm nerve models, respectively, which are well within established thresholds for nerve safety. These results suggest that these new electrodes can safely and successfully perform accurate PNI assessment without the presence of artifacts, with the potential to improve the INCS standard of care while remaining compatible with currently used neurosurgical technology, infrastructure, and clinical workflows. [ABSTRACT FROM AUTHOR]

Simple Summary: Intramedullary spinal cord melanocytomas are exceedingly rare. Here, we present a systematic review of the available literature and a case illustration from our surgical experience: a T1-weighted hyperintense lesion emerges with a focal contrast-enhancing nodule. Despite their benign histology, these tumors often present local aggressiveness with a high tendency towards local invasiveness, which is associated with frequent post-operative neurological deficits, and relapse, which eventually overwhelms adjuvant therapies, such as RT or salvage surgery. We present a case illustration of an intramedullary thoracic melanocytoma in a middle-aged woman. Despite the employment of complete intraoperative neuromonitoring and a frozen section, the adherence of the lesion to the surrounding spinal cord made it impossible to preserve neurological functioning. The current systematic review and case illustration highlight radiographic findings suspected of intramedullary melanocytoma, present the available surgical techniques, and address the importance of preserving neurological functions during the surgical treatment of intramedullary melanocytomas. Background: Intramedullary melanocytomas are exceedingly rare, with only twenty-four cases reported up to now. They present as local invasive tumors despite their benign biological behavior. Attempting a complete safe resection often results in severe post-operative neurological deficits, as in our case presented here. Methods: A systematic review was conducted across the PubMed and Scopus databases including studies published till February 2024. Results: A total of 19 studies were included, encompassing 24 cases. A similar distribution between sexes was noted (M:F 13:11), with ages ranging from 19 to 79 years. The thoracic segment was most affected, and intermediate-grade melanocytoma (19 cases) was the most common histotype. Radiographically, intramedullary melanocytomas usually appear as hyperintense hemorrhagic lesions peripheral to the central canal with focal nodular enhancement. Intraoperatively, they are black–reddish to tan and are tenaciously adherent lesions. In the sampled studies, IONM employment was uncommon, and post-operative new-onset neurological deficits were described in 16 cases. Adjuvant RT was used in four cases and its value is debatable. Recurrence is common (10 cases), and adjuvant therapies (RT or repeated surgery) seem to play a palliative role. Case presentation: A 68-year-old woman presented with a three-year history of worsening spastic paraparesis and loss of independence in daily activities (McCormick grade 4). An MRI revealed an intramedullary tumor from Th5 to Th7, characterized by T1-weighted hyperintensity and signs of recent intralesional hemorrhage. Multimodal neuromonitoring, comprising the D-Wave, guided the resection of a black–tan-colored tumor with hyper-vascularization and strong adherence to the white matter. During final dissection of the lesion to obtain gross total resection (GTR), a steep decline in MEPs and D-Wave signals was recorded. Post-operatively, the patient had severe hypoesthesia with Th9 level and segmental motor deficits, with some improvement during neurorehabilitation. Histopathology revealed an intermediate-grade melanocytoma (CNS WHO 2021 classification). A four-month follow-up documented the absence of relapse. Conclusions: This literature review highlights that intramedullary T1 hyperintense hemorrhagic thoracic lesions in an adult patient should raise the suspicion of intramedullary melanocytoma. They present as locally aggressive tumors, due to local invasiveness, which often lead to post-operative neurological deficits, and frequent relapses, which overwhelm therapeutic strategies leading to palliative care after several years. [ABSTRACT FROM AUTHOR]

Sensory peripheral neuropathy is a common complication of diabetes mellitus and the biggest risk factor for diabetic foot ulcers. There is currently no available treatment that can reverse sensory loss in the diabetic population. The application of mechanical noise has been shown to improve vibration perception threshold or plantar sensation (through stochastic resonance) in the short term, but the therapeutic use, and longer-term effects have not been explored. In this study, vibrating insoles were therapeutically used by 22 participants, for 30 min per day, on a daily basis, for a month by persons with diabetic sensory peripheral neuropathy. The therapeutic application of vibrating insoles in this cohort significantly improved VPT by an average of 8.5 V (p = 0.001) post-intervention and 8.2 V (p < 0.001) post-washout. This statistically and clinically relevant improvement can play a role in protection against diabetic foot ulcers and the delay of subsequent lower-extremity amputation. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer stands as a major public health concern worldwide, and a significant proportion of survivors are affected by recurrent and usually unrelieved cancer pain. The participation of ion channels in cancer pain's initiation and maintenance is well-described; however, the evidence on the contribution of transient receptor potential vanilloid 4 channels is scarce. The limited studies published to date encountered enhanced TRPV4 expression in cancer-induced bone pain (CIBP), perineural, and orofacial cancer models, increasing pain perception. These outcomes support the hypothesis that the modulation of TRPV4 channels can be targeted as a novel therapeutic approach for treating difficult pain. This review summarizes the role of TRPV4 in cancer etiology and cancer-induced pain mechanisms, as well as the current status of the clinical research. Despite the unique and complex nature of cancer pain, the activation of different ion channels can be related to the initiation and maintenance of pain. The transient receptor potential vanilloid 4 (TRPV4) is a cation channel broadly expressed in sensory afferent neurons. This channel is activated by multiple stimuli to mediate pain perception associated with inflammatory and neuropathic pain. Here, we focused on summarizing the role of TRPV4 in cancer etiology and cancer-induced pain mechanisms. Many studies revealed that the administration of a TRPV4 antagonist and TRPV4 knockdown diminishes nociception in chemotherapy-induced peripheral neuropathy (CIPN). Although the evidence on TRPV4 channels' involvement in cancer pain is scarce, the expression of these receptors was reportedly enhanced in cancer-induced bone pain (CIBP), perineural, and orofacial cancer models following the inoculation of tumor cells to the bone marrow cavity, sciatic nerve, and tongue, respectively. Effective pain management is a continuous problem for patients diagnosed with cancer, and current guidelines fail to address a mechanism-based treatment. Therefore, examining new molecules with potential antinociceptive properties targeting TRPV4 modulation would be interesting. Identifying such agents could lead to the development of treatment strategies with improved pain-relieving effects and fewer adverse effects than the currently available analgesics. [ABSTRACT FROM AUTHOR]

Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative–nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [Ca4Mn(DPDP)5; PledOx®], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying Ca4Mn(DPDP)5 in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with Ca4Mn(DPDP)5, a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with Ca4Mn(DPDP)5. The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca4Mn(DPDP)5 may be explained by redox interactions between Pt2+ and Mn2+ and subtle oxidative–nitrosative chain reactions. In peripheral sensory nerves, Pt2+ presumably leads to oxidation of the Mn2+ from Ca4Mn(DPDP)5 as well as from Mn2+ in MnSOD and other endogenous sources. Thereafter, Mn3+ may be oxidized by peroxynitrite (ONOO−) into Mn4+, which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O2•−) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt2+-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca4Mn(DPDP)5 mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt2+-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt2+ outcompetes Mn2+ and endogenous Zn2+ in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt2+ by DPDP, which in turn suggests that Mn2+ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN. [ABSTRACT FROM AUTHOR]

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant demyelinating neuropathy characterized by an increased susceptibility to peripheral nerve injury from trauma, compression, or shear forces. Patients with this condition are unique, necessitating distinct considerations for anesthesia and surgical teams. This review describes the etiology, prevalence, clinical presentation, and management of HNPP and presents contemporary evidence and recommendations for optimal care for HNPP patients in the perioperative period. While the incidence of HNPP is reported at 7–16:100,000, this figure may be an underestimation due to underdiagnosis, further complicating medicolegal issues. With the subtle nature of symptoms associated with HNPP, patients with this condition may remain unrecognized during the perioperative period, posing significant risks. Several aspects of caring for this population, including anesthetic choices, intraoperative positioning, and monitoring strategy, may deviate from standard practices. As such, a tailored approach to caring for this unique population, coupled with meticulous preoperative planning, is crucial and requires a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

Autosomal recessive Nonaka distal myopathy is a rare autosomal recessive genetic disease characterized by progressive degeneration of the distal muscles, causing muscle weakness and decreased grip strength. It is primarily associated with mutations in the GNE gene, which encodes a key enzyme of sialic acid biosynthesis (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase). This study was performed to find GNE mutations in six independent distal myopathy patients with or without peripheral neuropathy using whole-exome sequencing (WES). In silico pathogenic prediction and simulation of 3D structural changes were performed for the mutant GNE proteins. As a result, we identified five pathogenic or likely pathogenic missense variants: c.86T>C (p.Met29Thr), c.527A>T (p.Asp176Val), c.782T>C (p.Met261Thr), c.1714G>C (p.Val572Leu), and c.1771G>A (p.Ala591Thr). Five affected individuals showed compound heterozygous mutations, while only one patient revealed a homozygous mutation. Two patients revealed unreported combinations of combined heterozygous mutations. We observed some specific clinical features, such as complex phenotypes of distal myopathy with distal hereditary peripheral neuropathy, an earlier onset of weakness in legs than that of hands, and clinical heterogeneity between two patients with the same set of compound heterozygous mutations. Our findings on these genetic causes expand the clinical spectrum associated with the GNE mutations and can help prepare therapeutic strategies. [ABSTRACT FROM AUTHOR]

Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is released into the blood and cerebrospinal fluid after neuronal damage. There is a need for an early and sensitive blood biomarker for polyneuropathy, and this systematic review provides an overview on the value of NfL in the early detection of neuropathy, central nervous system involvement, the monitoring of neuropathy progression, and treatment effects in systemic amyloidosis. A literature search in PubMed, Embase, and Web of Science was performed on 14 February 2024 for studies investigating NfL levels in patients with systemic amyloidosis and transthyretin gene-variant (TTRv) carriers. Only studies containing original data were included. Included were thirteen full-text articles and five abstracts describing 1604 participants: 298 controls and 1306 TTRv carriers or patients with or without polyneuropathy. Patients with polyneuropathy demonstrated higher NfL levels compared to healthy controls and asymptomatic carriers. Disease onset was marked by rising NfL levels. Following the initiation of transthyretin gene-silencer treatment, NfL levels decreased and remained stable over an extended period. NfL is not an outcome biomarker, but an early and sensitive disease-process biomarker for neuropathy in systemic amyloidosis. Therefore, NfL has the potential to be used for the early detection of neuropathy, monitoring treatment effects, and monitoring disease progression in patients with systemic amyloidosis. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C virus (HCV) infection is characterized by a variety of extra-hepatic manifestations; peripheral neuropathy (PN) is one of the most common, especially when mixed cryoglobulinemia (MCG) is present. The prevalence and risk factors of HCV-related PN in the absence of MCG are largely unknown. We conducted a prospective, single-center study, examining the prevalence and reversibility of HCV-associated neuropathy in the absence of MCG. Nerve fiber density in the epidermis was evaluated through skin biopsy and electroneurography (ENG) before HCV-treatment initiation and 1 year post sustained virological remission (SVR). Forty HCV-infected individuals (nine HIV co-infected) with no other neuron-harming factors were included; four other HCV mono- and three HIV co-infected individuals were excluded due to presence of diabetes, B12 insufficiency, or neurotoxic drugs. Twelve consecutive controls with no neuron-harming conditions were also recruited; eight more were excluded due to meeting exclusion criteria. Four patients had ENG signs of polyneuropathy (two with HCV mono- and two with HIV co-infection), while seven more (five with HCV mono- and two with HIV co-infection) had signs of mono-neuropathy, leading to PN prevalences of 22.5% and 44% for mono- and co-infection, respectively (p value 0.179). The two patients with HCV mono-infection and polyneuropathy and the one with ulnar nerve damage showed ENG improvement 1 year post SVR. Regarding intraepidermal nerve density, HCV infection, irrespective of HIV co-infection, was correlated with a lower intraepidermal neuron density that improved 1 year post SVR (p value 0.0002 for HCV and 0.0326 for HCV/HIV co-infected patients). PN is common in HCV infection; successful eradication of HCV leads to PN improvement. [ABSTRACT FROM AUTHOR]

Many anti-cancer drugs, such as taxanes, platinum compounds, vinca alkaloids, and proteasome inhibitors, can cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a frequent and harmful side effect that affects the sensory, motor, and autonomic nerves, leading to pain, numbness, tingling, weakness, and reduced quality of life. The causes of CIPN are not fully known, but they involve direct nerve damage, oxidative stress, inflammation, DNA damage, microtubule dysfunction, and altered ion channel activity. CIPN is also affected by genetic, epigenetic, and environmental factors that modulate the risk and intensity of nerve damage. Currently, there are no effective treatments or prevention methods for CIPN, and symptom management is mostly symptomatic and palliative. Therefore, there is a high demand for better understanding of the cellular and molecular mechanisms involved in CIPN, as well as the development of new biomarkers and therapeutic targets. This review gives an overview of the current knowledge and challenges in the field of CIPN, focusing on the biological and molecular mechanisms underlying this disorder. [ABSTRACT FROM AUTHOR]

Widespread contamination of the Amazon basin with mercury has been reported to occur since at least the mid-80s due to heavy gold mining activity. Although initial studies have indicated that this may lead to deleterious neurological consequences to the indigenous populations living in the region, further research is needed to better characterize the neurological burden of such long-term exposure. With this aim, a cross-sectional exploratory study has been conducted with the Yanomami indigenous population residing in a northern Amazon region. All participants underwent a structured interview; detailed neurological examination, including assessment for cognitive, motor, coordination, and sensory functions; and laboratorial testing for serum hemoglobin, blood glucose, and methylmercury levels in hair samples. This study enrolled 154 individuals of 30.9 ± 16.8 years of age, of which 56.1% were female. Mean methylmercury levels in hair were 3.9 ± 1.7 µg/g. Methylmercury levels in hair > 6.0 µg/g were found in 10.3%. Among participants with hair methylmercury levels ≥ 6.0 μg/g, the prevalences of peripheral neuropathy and reduced cognitive performance were, respectively, 78.8% (95%CI 15–177%, p = 0.010) and 95.9% (95%CI 16–230.8%, p = 0.012) higher than those of individuals with lower levels. These results suggest that chronic mercury exposure may lead to significant and potentially irreversible neurotoxicity to Yanomami population living in the northern Amazon basin. [ABSTRACT FROM AUTHOR]

Background and Objectives: Diabetic peripheral neuropathy (DPN) affects approximately half of patients with diabetes mellitus (DM), contributing to falls and fractures. Oxidative stress, which is linked to DM-induced hyperglycemia, has been implicated in the onset of DPN. Although exercise is recommended for patients with DM, its effect on DPN remains unclear. Therefore, this study aimed to investigate the effect of exercise on DPN and the mechanisms involved. Material and Methods: Thirty male Wistar rats were divided into control, streptozotocin (STZ)-induced diabetic (DM), and STZ-induced diabetic/exercise (DM + Ex) groups. Diabetes was induced using STZ injection. Rats in the DM + Ex groups underwent six weeks of treadmill exercise. Sciatic nerve parameters, which included motor nerve conduction velocity (MNCV), antioxidant enzymes (catalase, glutathione peroxidase [GPx], and superoxide dismutase [SOD]), oxidative stress markers (malondialdehyde [MDA] and 4-hydroxy-2-nonenal [4HNE]), and neurotrophic factors (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]), were examined. Results: Exercise alleviated DM-induced decreases in MNCV in rats. Although exercise did not significantly affect antioxidant enzyme activity, 4HNE levels increased significantly, indicating increased oxidative stress. Additionally, exercise did not significantly affect DM-induced increases in NGF and BDNF levels in rats. Conclusions: Exercise may prevent DPN in rats with DM, possibly through nonantioxidant mechanisms. [ABSTRACT FROM AUTHOR]

The peripheral nervous system undergoes sufficient stress when affected by diabetic conditions, chemotherapeutic drugs, and personal injury. Consequently, peripheral neuropathy arises as the most common complication, leading to debilitating symptoms that significantly alter the quality and way of life. The resulting chronic pain requires a treatment approach that does not simply mask the accompanying symptoms but provides the necessary external environment and neurotrophic factors that will effectively facilitate nerve regeneration. Under normal conditions, the peripheral nervous system self-regenerates very slowly. The rate of progression is further hindered by the development of fibrosis and scar tissue formation, which does not allow sufficient neurite outgrowth to the target site. By incorporating scaffolding supplemented with secretome derived from human mesenchymal stem cells, it is hypothesized that neurotrophic factors and cellular signaling can facilitate the optimal microenvironment for nerve reinnervation. However, conventional methods of secretory vesicle production are low yield, thus requiring improved methods to enhance paracrine secretions. This report highlights the state-of-the-art methods of neuropathy treatment as well as methods to optimize the clinical application of stem cells and derived secretory vesicles for nerve regeneration. [ABSTRACT FROM AUTHOR]

Simple Summary: Cisplatin is a chemotherapy drug extensively used to treat cancer, improving the survival of cancer patients. Although effective for this purpose, its use is accompanied by notorious severe adverse effects that significantly reduce patient's quality of life. This review will discuss the main impact of chemotherapy on the peripheral nervous system, a clinical condition known as chemotherapy-induced peripheral neuropathy, with emphasis on cisplatin. Furthermore, the review encompasses an analysis of the role played by G protein-coupled receptors and ion channels in cisplatin-induced peripheral neuropathy, extracting insights from preclinical experimental studies. Cisplatin is a platinum-based chemotherapy drug widely used to treat various solid tumours. Although it is effective in anti-cancer therapy, many patients develop peripheral neuropathy during and after cisplatin treatment. Peripheral neuropathy results from lesions or diseases in the peripheral somatosensory nervous system and is a significant cause of debilitation and suffering in patients. In recent years, preclinical studies have been conducted to elucidate the mechanisms involved in chemotherapy-induced peripheral neuropathic pain, as well as to promote new therapeutic targets since current treatments are ineffective and are associated with adverse effects. G-protein coupled receptors and ion channels play a significant role in pain processing and may represent promising targets for improving the management of cisplatin-induced neuropathic pain. This review describes the role of G protein-coupled receptors and ion channels in cisplatin-induced pain, analysing preclinical experimental studies that investigated the role of each receptor subtype in the modulation of cisplatin-induced pain. [ABSTRACT FROM AUTHOR]

Among the vinca-alkaloid class, vincristine is a potent chemotherapeutic agent with significant neurotoxic effects and is employed to address a wide spectrum of cancer types. Recently, the therapeutic potential of the cholecystokinin type 2 receptor (CCK2R) as a target for vincristine-induced peripheral neuropathy (VIPN) was demonstrated. In this study, the impact of preventive CCK2R blockade using netazepide (Trio Medicines Ltd., London, UK) was investigated in a mouse model of vincristine-induced peripheral neuropathy. Netazepide is a highly selective CCK2R antagonist under development for the treatment of patients with gastric neuroendocrine tumors caused by hypergastrinemia secondary to chronic autoimmune atrophic gastritis. Vincristine-induced peripheral neuropathy was induced by intraperitoneal injections of vincristine at 100 µg/kg/d for 7 days (D0 to D7). Netazepide (2 mg/kg/d or 5 mg/kg/d, per os) was administered one day before vincristine treatment until D7. Vincristine induced a high tactile allodynia from D1 to D7. VIPN was characterized by dorsal root ganglion neuron (DRG) and intraepidermal nerve fiber (IENF) loss, and enlargement and loss of myelinated axons in the sciatic nerve. Netazepide completely prevented the painful symptoms and nerve injuries induced by vincristine. In conclusion, the fact that netazepide protected against vincristine-induced peripheral neuropathy in a mouse model strongly supports the assessment of its therapeutic potential in patients receiving such chemotherapy. [ABSTRACT FROM AUTHOR]

Distal Sensory Peripheral Neuropathy (DSP) is a common complication in HIV-infected individuals, leading to chronic pain and reduced quality of life. Even with antiretroviral therapy (ART), DSP persists, often prompting the use of opioid analgesics, which can paradoxically worsen symptoms through opioid-induced microbial dysbiosis. This study employs the HIV Tg26 mouse model to investigate HIV-DSP development and assess gut microbiome changes in response to chronic morphine treatment and ART using 16S rRNA sequencing. Our results reveal that chronic morphine and ART exacerbate HIV-DSP in Tg26 mice, primarily through mechanical pain pathways. As the gut microbiome may be involved in chronic pain persistence, microbiome analysis indicated distinct bacterial community changes between WT and Tg26 mice as well as morphine- and ART-induced microbial changes in the Tg26 mice. This study reveals the Tg26 mouse model to be a relevant system that can help elucidate the pathogenic mechanisms of the opioid- and ART-induced exacerbation of HIV-associated pain. Our results shed light on the intricate interplay between HIV infection, ART, opioid use, and the gut microbiome in chronic pain development. They hold implications for understanding the mechanisms underlying HIV-associated pain and microbial dysbiosis, with potential for future research focused on prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Patients with peripheral neuropathy with type 2 diabetes mellitus (T2DM) are more likely to have functional impairments. Recently, the gene for serum sterile alpha and toll/interleukin receptor motif-containing protein 1 (SARM1), which may contribute to the pathogenesis of Wallerian degeneration, was discovered in mice models of peripheral neuropathy. We set out to assess serum SARM1's activity as a potential biomarker for the early identification of diabetic peripheral neuropathy in T2DM patients while also examining the impact of the COVID-19 vaccine on SARM1 levels. We assessed the cross-sectional relationships between the SARM1 biomarker, clinical neuropathy scales, and nerve conduction parameters in 80 participants aged between 30 years and 60 years. The analysis was carried out after the patients were split into two groups since we discovered a significant increase in SARM1 levels following the second dose of the COVID-19 vaccination, where group A received one dose of the COVID-19 vaccine inoculation, and group B received two doses of the COVID-19 vaccine. SARM1 was correlated significantly (p < 0.05) with MNSIe and NSS in group A and showed a consistent positive correlation with the other neuropathy clinical scales in group A and group B without reaching statistical significance. Additionally, SARM1 was negatively correlated significantly (p < 0.05) with the median sensory amplitude in group A and showed a consistent negative correlation with the six other sensory and motor nerves' potential amplitude in group A and group B without reaching statistical significance. In conclusion, SARM1 showed a consistent correlation with clinical neuropathy scales and nerve conduction parameters after accounting for the influence of COVID-19 vaccination doses. [ABSTRACT FROM AUTHOR]