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Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect ∼10 000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord −/−, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioural tests as well as biochemical, physiological and comprehensive histological examinations. Sord −/− rats had remarkably increased levels of sorbitol in serum, CSF and peripheral nerve. Moreover, serum from Sord −/− rats contained significantly increased levels of neurofilament light chain, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord −/− animals starting at ∼7 months of age. Gait analysis evaluated with video motion-tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding—enlarged 'ballooned' myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord −/− rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy. [ABSTRACT FROM AUTHOR]

Background and Aims: Prior to next‐generation sequencing (NGS), the evaluation of a patient with neuropathy typically consisted of screening for acquired causes, followed by clinical genetic testing of PMP22, MFN2, GJB1, and MPZ in patients with a positive family history and symptom onset prior to age 50. In this study, we examined the clinical utility of NGS in a large cohort of patients analyzed in a commercial laboratory. Methods: A cohort of 6849 adult patients underwent clinician‐ordered peripheral neuropathy multigene panel testing ranging from 66 to 111 genes that included NGS and intragenic deletion/duplication analysis. Results: A molecular diagnosis was identified for 8.4% of the cohort (n = 573/6849). Variants in PMP22, MFN2, GJB1, MPZ, and TTR accounted for 73.8% of molecular diagnoses. Results had potential clinical actionability for 398 (69.5%) patients. Our results suggest that 225/573 (39.3%) of molecular diagnoses and 113/398 (28.4%) of clinical interventions would have been missed if the testing approach had been restricted to older guidelines. Interpretation: Our results highlight the need for expanded genetic testing guidelines that account for the increased number of genes associated with hereditary neuropathy, address the overlap of acquired and hereditary neuropathy, and provide broader access to genetic diagnosis for patients. [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the major side effects and main reasons for affecting quality of life and dose reduction or even discontinuation of treatment in breast cancer patients. One of the most widely prescribed chemotherapies is the "taxanes." Considering that duloxetine has been used in treating neuropathies in recent years, this study aimed to investigate its effectiveness in preventing taxane-related neuropathy. Material and methods: This is a randomized controlled trial on 47 patients: 24 received a placebo and 23 received duloxetine at 30 mg daily in the first week following the injection of paclitaxel and 60 mg during the second week in each chemotherapy cycle. Patients objective (nerve conduction velocity (NCV) values) and subjective symptoms (visual analog scale including; neuropathy, paresthesia, pain, cold sensitivity, and numbness), the grades of the patients' neuropathy (calculated according to Common Terminology Criteria for Adverse Events (CTCAE) v.5), and the presence of complications, before and after each chemotherapy cycle, were recorded. Results: The placebo group experienced significantly higher occurrences of new neuropathy (8/23 in duloxetine vs 16/24 in placebo, P = 0.029) in NCV by tibial nerve latency (− 0.28% vs 19.87%, P = 0.006), tibial amplitude (4.40% vs − 10.88%, P = 0.049), and median nerve latency (8.72% vs 31.16%, P = 0.039); administration of duloxetine significantly reduced the scores of neuropathies (P < 0.001), pain (P = 0.027), during chemotherapy, and 6 weeks later; however, no significant effect was observed on paresthesia, numbness, cold sensitivity, and other NCV measurements. Conclusions: Paclitaxel can cause neuropathy, lasting for a long time. Our study showed duloxetine is potentially an effective medication that can prevent subjective and objective neuropathy. [ABSTRACT FROM AUTHOR]

Objective: To determine the inter-reader reliability and diagnostic performance of classification and severity scales of Neuropathy Score Reporting And Data System (NS-RADS) among readers of differing experience levels after limited teaching of the scoring system. Methods: This is a multi-institutional, cross-sectional, retrospective study of MRI cases of proven peripheral neuropathy (PN) conditions. Thirty-two radiology readers with varying experience levels were recruited from different institutions. Each reader attended and received a structured presentation that described the NS-RADS classification system containing examples and reviewed published articles on this subject. The readers were then asked to perform NS-RADS scoring with recording of category, subcategory, and most likely diagnosis. Inter-reader agreements were evaluated by Conger's kappa and diagnostic accuracy was calculated for each reader as percent correct diagnosis. A linear mixed model was used to estimate and compare accuracy between trainees and attendings. Results: Across all readers, agreement was good for NS-RADS category and moderate for subcategory. Inter-reader agreement of trainees was comparable to attendings (0.65 vs 0.65). Reader accuracy for attendings was 75% (95% CI 73%, 77%), slightly higher than for trainees (71% (69%, 72%), p = 0.0006) for nerves and comparable for muscles (attendings, 87.5% (95% CI 86.1–88.8%) and trainees, 86.6% (95% CI 85.2–87.9%), p = 0.4). NS-RADS accuracy was also higher than average accuracy for the most plausible diagnosis for attending radiologists at 67% (95% CI 63%, 71%) and for trainees at 65% (95% CI 60%, 69%) (p = 0.036). Conclusion: Non-expert radiologists interpreted PN conditions with good accuracy and moderate-to-good inter-reader reliability using the NS-RADS scoring system. Clinical relevance statement: The Neuropathy Score Reporting And Data System (NS-RADS) is an accurate and reliable MRI-based image scoring system for practical use for the diagnosis and grading of severity of peripheral neuromuscular disorders by both experienced and general radiologists. Key Points: • The Neuropathy Score Reporting And Data System (NS-RADS) can be used effectively by non-expert radiologists to categorize peripheral neuropathy. • Across 32 different experience-level readers, the agreement was good for NS-RADS category and moderate for NS-RADS subcategory. • NS-RADS accuracy was higher than the average accuracy for the most plausible diagnosis for both attending radiologists and trainees (at 75%, 71% and 65%, 65%, respectively). [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]

Background: Diabetic peripheral neuropathy (DPN) occurs in >50% of diabetic patients and is a high risk‐factor of balance problems and risk of falls. Impaired balance can lead to reduced function, which has a detrimental effect on patients' quality of life. Structured strength and balance training can result in sustained improvements in muscle strength, coordination, balance, functional status and quality of life. Objective: To determine the combined effects of strength and balance training versus aerobic training on balance, severity of symptoms of DPN, and quality of life in patients with DPN. Methods: This double blinded, two arm parallel design Randomized Clinical Trial. The study was conducted from March to December 2020 in the AIMS diabetic center Peshawar, Pakistan. Participants were selected through convenience sampling technique and randomly allocated into strength plus balance and aerobic training groups. Type 2 diabetic patients of both sexes, aged 40 to 80 years, with a Toronto neuropathy score ≥6 recruited, while patients with ulceration/infection of feet, medical/Surgical conditions, and non‐ambulatory patients were excluded from this study. Intervention was applied 3 days a week for 8 weeks. The Toronto clinical neuropathy system was used to assess neuropathy severity, SF‐36 to assess quality of life and the Berg balance scale was used for assessment of balance. Assessment was done at the baseline and after 8 weeks of intervention using SPSS. Version 22 was used for analysis. Results: The mean age of the participants was 60.80 ± 9.73. Between group analysis, which showed were statistically insignificant for neuropathy severity, balance and all domains of quality of life (p‐value >0.05) except SF‐36 General Health Perception Score, with Mean ± SD of 62.50 ± 7.54 in group A versus Mean ± SD of in group B 60.00 ± 15.98 (p‐value = 0.05). Within group analysis showed statistically significant results for neuropathy severity, balance and all domains of quality of life (p‐value<0.05). Conclusion: This study concluded that there is a statistically significant effect of structured balance and strength training and aerobic training on severity of DPN, balance and quality of life. But there was no statistically significant difference in improvement between the two intervention groups. [ABSTRACT FROM AUTHOR]

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Background: Paclitaxel administration is considered a keystone in the management of many types of cancers. However, paclitaxel chemotherapy often leads to peripheral neuropathy which is the most prominent adverse effect that reduces the patient's quality of life and demands dose reduction leading to decreased disease curing. Paclitaxel induces peripheral neuropathy through disruption of microtubules, distorted function of ion channels, axonal degeneration, and inflammatory events. So far, there is no standard medication to prevent the incidence of paclitaxel-induced peripheral neuropathy (PIPN). Main body: Numerous preclinical studies in rats and rodents showed that several therapeutic agents have neuroprotective mechanisms and reduce the incidence of PIPN, proving their effectiveness in the prevention of PIPN in animal models. Different mechanisms, such as reduction of the expression of inflammatory mediators, quenching of reactive oxygen species, prevention of neuronal damage, and other mechanisms, have been explored. Moreover, many clinical trials have further established the neuroprotective effect of several investigational drugs on PIPN. Twenty preclinical studies of pharmacological interventions were reviewed for their preventive effect on neuropathy. These medications targeted cannabinoid receptors, oxidative stress, inflammatory response, and ion channels. Additionally, 25 clinical studies with pharmacological preventive interventions of PIPN have been reviewed, of which only 10 showed preventive action in PIPN. Conclusion: Prevention of PIPN is currently considered an emergent field of research. This review highlights the potential interventions and presents recent findings from both preclinical and clinical studies on the significant prevention of PIPN to help in effective decision-making. However, further well-designed research is required to ascertain recommendations for clinical practice. [ABSTRACT FROM AUTHOR]

Purpose of Review: Diabetic neuropathy is a debilitating complication of diabetes mellitus that affects millions of individuals worldwide. It is characterized by nerve damage resulting from prolonged exposure to high blood glucose levels. Diabetic neuropathy may cause a range of symptoms, including pain, numbness, muscle weakness, autonomic dysfunction, and foot ulcers, potentially causing significant impairment to the quality of life for those affected. This review article aims to provide a comprehensive overview of the pathophysiology of diabetic neuropathy. The etiology of diabetic neuropathy will be discussed, including risk factors, predisposing conditions, and an overview of the complex interplay between hyperglycemia, metabolic dysregulation, and nerve damage. Additionally, we will explore the molecular mechanisms and pathways of diabetic neuropathy, including the impact of hyperglycemia on nerve function, abnormalities in glucose metabolism, the role of advanced glycation end products (AGEs), and inflammatory and immune-mediated processes. We will provide an overview of the various nerve fibers affected by diabetic neuropathy and explore the common symptoms and complications associated with diabetic neuropathy in the pain medicine field. Recent Findings: This review highlights advances in understanding the pathophysiology of diabetic neuropathy as well as reviews potential novel therapeutic strategies and promising areas for future research. Summary: In conclusion, this review article aims to shed light on the pathophysiology of diabetic neuropathy, its far-reaching consequences, and the evolving strategies for prevention and management. In understanding the mechanisms of diabetic neuropathy and the ongoing research in this area, healthcare professionals can better serve patients with diabetes, ultimately improving well-being and reducing complications. [ABSTRACT FROM AUTHOR]

Background: Paclitaxel administration causes peripheral neuropathy. Auraptene is a natural bioactive monoterpene with anti-inflammatory and anti-neuropathic effects that is widely used. Objectives: We aimed to study auraptene effects on paclitaxel-induced neuropathy. Materials and Methods: This study was comprised of two steps of evaluation of the preventive and treatment effects of auraptene in mice. In the first step, mice were randomly allocated into three groups of six animals, including the negative control (NEG CTL): animals injected with paclitaxel (PTX) together with normal saline, PTX (paclitaxel 2 mg/kg given on days 1, 3, 5, and 7), and PREVENTION: PTX + auraptene 100 mg/kg on days 1, 3, 5, and 7. In the second step, animals were allocated into six groups of six: NEG CTL (normal saline), PTX (paclitaxel 10 mg/kg given on days 1, 3, 5, and 7), PTX AUR (PTX + auraptene 50, 75, and 100 mg/kg), and a positive control (PTX-treated animals receiving imipramine 10 mg/kg). Intraperitoneal injection of PTX 2 mg/kg on days 1, 3, 5, and 7 was used in order to induce neuropathy. In both steps of the study, a hot plate test was done on day 7 in order to determine the response to heat. After the scarification of animals, the interleukin-6 (IL-6) level in the sciatic nerve was assessed by western blotting. Results: In the preventive group, auraptene could reduce hyperalgesia significantly. In the treatment step, the AUR 100 mg/kg compared to NEG CTL groups had significantly increased heat latency. The expression of IL-6 protein in the sciatic nerve was remarkably decreased in both the preventive and treatment groups compared to NEG CTL. Conclusion: Taken together, our results confirmed that AUR could decrease paclitaxel-induced hyperalgesia in mice and IL-6 protein content in sciatic nerve samples. [ABSTRACT FROM AUTHOR]

Background Vitamin B12 deficiency has been associated with significant neurological pathology, especially peripheral neuropathy. Combination medicines and pure methylcobalamin seems to improve symptoms rather than electrophysiologic outcomes in individuals with diabetic peripheral neuropathy. The aim of present study was to assess the effect of Vitamin B supplementation for diabetic peripheral neuropathy. Methods The present cross-sectional study was conducted at department of general medicine among 100 patients with diabetic peripheral neuropathy who visited during the study period of one year. Patients were divided into two groups (group B and group P). The entire neuropathy and laboratory test were done. With IBM SPSS v25.0, statistical analyses were carried out. Results There were no significant differences between the group B and group P regarding demographics, anthropometric and laboratory measurements. Vitamin B12 levels significantly increased in the group B from 237.8±70.3 pmol/L at baseline to 775.8±234.2 pmol/L at follow-up. In the group B, there was a significant improvement in the vibration perception threshold (VPT), MNSIQ, pain score, quality of life (QoL), sural nerve conduction velocity (SNCV), sural nerve action potential (amplitude) (SNAP), and electrochemical skin conductance in feet (ESCF) during the follow-up (p =0.001, p = 0.003, p = 0.0001, p = 0.0001, and p = 0.013, respectively). Conclusion Patients with DN who received an oral methylcobalamin treatment for a whole year had improvements in their QoL, pain score, sudomotor function, plasma B12 levels, and all neurorophysiological markers; however, CARTS and MNSIE did not show any improvement. [ABSTRACT FROM AUTHOR]

Aim: Acute lymphoblastic leukaemia (ALL) therapy has been associated with a significant burden of toxicities. The aim of this study was to describe the full spectrum of toxic effects associated with childhood ALL. Methods: Toxicity‐related data were collected from the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL‐2008 toxicity registry, in which data on 19 clinically relevant toxicities were registered during ALL treatment, and from patient medical records. All patients treated according to the NOPHO ALL‐2008 protocol in Oulu University Hospital between 2008 and 2020 were included in the study. Results: The cohort consisted of 73 patients, 38 of whom were male. Mean age at diagnosis was 6.6 ± 4.2 (range 1.4–16.0) years. All but one of the patients developed at least one treatment‐related toxicity and more than half had multiple toxicities. Female sex and older age were associated with a higher tendency towards toxicity. The most common toxicity was vincristine‐induced peripheral neuropathy, which was observed in 70 patients. Most toxicities were moderate or severe, but even mild toxicities often affected leukaemia treatment. Conclusion: Moderate and severe treatment‐related toxicities are common, and most toxicities occur in a typical pattern in relation to the treatment phases. [ABSTRACT FROM AUTHOR]

We are engaged in the development and clinical application of a neural magnetic field measurement system that utilizes biomagnetic measurements to observe the activity of the spinal cord and peripheral nerves. Unlike conventional surface potential measurements, biomagnetic measurements are not affected by the conductivity distribution within the body, making them less influenced by the anatomical structure of body tissues. Consequently, functional testing using biomagnetic measurements can achieve higher spatial resolution compared to surface potential measurements. The neural magnetic field measurement, referred to as magnetoneurography, takes advantage of these benefits to enable functional testing of the spinal cord and peripheral nerves, while maintaining high spatial resolution and noninvasiveness. Our magnetoneurograph system is based on superconducting quantum interference devices (SQUIDs) similar to the conventional biomagnetic measurement systems. Various design considerations have been incorporated into the SQUID sensor array structure and signal processing software to make it suitable for detecting neural signal propagation along spinal cord and peripheral nerve. The technical validation of this system began in 1999 with a 3-channel SQUID system. Over the course of more than 20 years, we have continued technological development through medical-engineering collaboration, and in the latest prototype released in 2020, neural function imaging of the spinal cord and peripheral nerves, which could also be applied for the diagnosis of neurological disorders, has become possible. This paper provides an overview of the technical aspects of the magnetoneurograph system, covering the measurement hardware and software perspectives for providing diagnostic information, and its applications. Additionally, we discuss the integration with a helium recondensing system, which is a key factor in reducing running costs and achieving practicality in hospitals. [ABSTRACT FROM AUTHOR]

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 patient's 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. [ABSTRACT FROM AUTHOR]

Background: Accelerated neuropathy is a rare syndrome of rapidly worsening peripheral neuropathy, typically described in end‐stage kidney disease (ESKD) patients undergoing dialysis. In our center, we encountered a surge in the occurrence of accelerated neuropathy among ESKD patients undergoing hemodialysis, which prompted systematic research. Methods: In this case–control study, we present the clinical features, electrophysiologic findings, and outcome of a series of patients who developed accelerated neuropathy after commencing hemodialysis for ESKD. Those who initiated hemodialysis and did not develop accelerated neuropathy were included as controls. We used logistic regression to identify predictors of accelerated neuropathy. Results: Among 436 ESKD patients who initiated hemodialysis over 4 years, 17 were diagnosed with accelerated neuropathy. The median‐time (interquartile range) from hemodialysis initiation to presentation with accelerated neuropathy was 3 weeks (2–6). It typically presented as acute onset of unsteadiness of gait necessitating assistance for ambulation. Electrophysiology revealed length‐dependent symmetric sensorimotor axonal neuropathy. Diabetes mellitus (odds ratio [OR] 4.1, 95% CI 1.2–13.9, p = 0.02), pre‐existing peripheral neuropathy (OR 9.25, 95% CI 2.79–30.6, p < 0.001), and serum alkaline phosphatase (OR 1.2 for every 10 U increase, 95% CI 1.00–1.52, p = 0.04) significantly predicted accelerated neuropathy. With continued dialysis and supportive care, neurologic status improved, total‐neuropathy score (summary score of peripheral nerve dysfunction incorporating clinical and electrophysiological parameters) declined from 26.5 to 18.4 (p < 0.001) and most regained unassisted ambulation. Conclusion: This study presents the largest series of patients with accelerated neuropathy and has identified predictors. However, in view of the unusually high incidence of accelerated neuropathy we speculate that other unidentified factor(s) could be underlying its pathogenesis. [ABSTRACT FROM AUTHOR]

Autoimmune nodopathies are inflammatory diseases of the peripheral nervous system with clinical and neurophysiological peculiar characteristics. In this nosological category, we find patients with autoantibodies against Neurofascin 140/186 and 155, Contactin1, and Caspr1 directed precisely towards nodal and paranodal structures. These antibodies are extremely rare and cause severe clinical symptoms. We describe the clinical case of a patient with autoimmune nodopathy caused by the coexistence of anti-neurofascin (NF) 186/140 and 155, characterized by progressive weakness in all limbs leading to tetraplegia, involving cranial nerves, and respiratory insufficiency. Response to first-line treatments was good followed by rapid dramatic clinical relapse. There are few reported cases of anti-pan NF neuropathy in the literature, and they present a clinical phenotype similar to our patient. In these cases, early recognition of clinical red flags of nodopathies and serial neurophysiological studies can facilitate the diagnosis. However, the severe clinical relapse suggests a possible early use of immunosuppressive therapies for this rare category of patients. [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]

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant cancer treatment side effect that can influence both quality of life and treatment course. Melissa Officinalis (MO), due to its high content of flavonoids, has antioxidant, anti-inflammatory, and neuroprotective properties. Materials and Methods: The cancer patients diagnosed with CIPN attended a referral center in Sari (Iran). The hydroalcoholic extract of MO leaves was extracted by the maceration method. The control group received a placebo along with gabapentin as the standard treatment, and the intervention group received 500 mg Melissa officinalis 2 times daily for 3 months plus gabapentin. Patients were evaluated at the baseline and 3 months later, according to Common Terminology Criteria for Adverse Effects (CTCAE) and EORTC QLQ-C30 (Integrated System for Quality of Life Assessment). Results: A total of 40 patients were considered as group D (intervention group), and 35 patients completed the study. Out of 40 subjects in the placebo group (P), 3 patients could not tolerate the drug due to gastrointestinal disturbances. The final values of CTCAE showed a statistically significant difference (p=0.010). Indicators related to the quality of life in both groups showed a significant improvement. In the intervention group, the pain perception and diarrhea experience were significantly reduced. Conclusion: Quality of life indicators were improved by prescribing gabapentin with and without Melissa officinalis. The addition of Melissa officinalis to the chemotherapy regimen may improve diarrhea and pain perception. [ABSTRACT FROM AUTHOR]

Background and Aims: Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain. Methods: We conducted unbiased mass‐spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein–protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross‐validation and bootstrapping. Results: In the univariate analysis, 73 proteins showed a p‐value <.05 and 12 proteins showed a p‐value <.01. None were significant after Benjamini–Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false‐negative rate 0.10, false‐positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini–Hochberg adjusted p‐value =.0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin‐like growth factor‐binding protein 2 (IGFBP2), complement factor H‐related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified. Interpretation: This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN. [ABSTRACT FROM AUTHOR]

The objective is to investigate the presentation, complications, management, and outcomes of copper deficiency-induced neurological pathologies due to Wilson disease (WD) overtreatment. We examined the case of a WD patient who developed a low thoracic dorsal myelopathy due to chronic hypocupremia from excessive zinc therapy. A comprehensive literature review was conducted to identify similar cases. Ten additional cases of neurological pathology resulting from copper deficiency in the context of WD over-treatment were identified, all occurring during therapy with zinc salts. Myelopathy and peripheral neuropathy were the most common complications, while two additional groups reported leukoencephalopathy. Early cytopenia was often associated with copper deficiency-related neurological pathology appearing early in the context of copper deficiency. WD patients undergoing treatment, especially with zinc salts, should be closely monitored to prevent over-treatment and the consequent copper deficiency. Regular complete blood counts could provide early detection of copper deficiency, avoiding irreversible neurological damage. Swift recognition of new neurological signs not consistent with WD and timely discontinuation of the decoppering therapy are critical for improving outcomes. The optimal management, including the potential benefit of copper supplementation in patients with WD and subsequent therapy adjustments, remains unclear and necessitates further investigation. Despite the general poor functional neurological outcomes, there were some exceptions that warrant further exploration. [ABSTRACT FROM AUTHOR]

Aims Chronic alcohol consumption is well known to cause peripheral neuropathy, affecting both small and large nerve fibers. The aim of this study was to correlate biochemical and neurophysiological findings and investigate possible biomarkers and risk factors for pathogenetic mechanisms of neuropathy in patients diagnosed with alcohol use disorder (AUD). Methods Ninety patients diagnosed with AUD were enrolled in this prospective study over a period of 3 years. Serum biochemical parameters, as well as thiamine blood levels, were determined upon admission. Every subject was assessed by clinical neurological examination, followed by Nerve Conduction Studies, Quantitative Sensory Testing, and Sympathetic Skin Response. Fifty age and gender-matched patients without a diagnosis of AUD were used as the control group. Results Peripheral neuropathy was diagnosed in 54 patients (60%). Among them, pure large fiber neuropathy was found in 18 patients, pure small fiber neuropathy in 12 patients, and both large and small fiber neuropathy was diagnosed in 24 patients. Elevated liver enzymes and fasting glucose levels upon admission were significantly correlated with neuropathy. Lower blood thiamine levels (than reference) were found in seven patients and were not correlated with neuropathy. Conclusions Our study suggests that alcohol-related liver dysfunction and hyperglycemia may contribute as risk factors of peripheral neuropathy in patients diagnosed with AUD, while blood thiamine levels do not correlate with neuropathy. Moreover, we suggest that liver enzymes and the De Ritis ratio could be potentially used as biomarkers for the incidence and severity of alcohol-related neuropathy. [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]

Purpose: Diabetic neuropathy can lead to decreased peripheral sensation and motor neuron dysfunction associated with impaired postural control and risk of falling. However, the relationship between decreased peripheral sensation and impaired vestibular function in diabetes mellitus is poorly investigated. Therefore, the aim of this study was to investigate the relationship between peripheral and autonomic measurements of diabetic neuropathy and measurements of vestibular function. Methods: A total of 114 participants with type 1 diabetes (n = 52), type 2 diabetes (n = 51) and controls (n = 11) were included. Vestibular function was evaluated by video head impulse testing. Peripheral neuropathy was assessed by quantitative sensory testing and nerve conduction. Autonomic neuropathy using the COMPASS 31 questionnaire. Data were analyzed according to data type and distribution. Results: Measurements of vestibular function did not differ between participants with type 1 diabetes, type 2 diabetes or controls (all p-values above 0.05). Subgrouping of participants according to the involvement of large-, small- or autonomic nerves did not change this outcome. Correlation analyses showed a significant difference between COMPASS 31 and right lateral gain value (ρ = 0.23, p = 0.02,), while no other significant correlations were found. Conclusion: Diabetic neuropathy does not appear to impair vestibular function in diabetes, by means of the VOR. Clinical trials: NCT05389566, May 25th, 2022. [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]

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]

Background: Chemotherapy‐induced peripheral neuropathy (CIPN) includes negative sensations that remain a major chronic problem for cancer survivors. Previous research demonstrated that neurofeedback (a closed‐loop brain–computer interface [BCI]) was effective at treating CIPN versus a waitlist control (WLC). The authors' a priori hypothesis was that BCI would be superior to placebo feedback (placebo control [PLC]) and to WLC in alleviating CIPN and that changes in brain activity would predict symptom report. Methods: Randomization to one of three conditions occurred between November 2014 and November 2018. Breast cancer survivors no longer in treatment were assessed at baseline, at the end of 20 treatment sessions, and 1 month later. Auditory and visual rewards were given over 20 sessions based on each patient's ability to modify their own electroencephalographic signals. The Pain Quality Assessment Scale (PQAS) at the end of treatment was the primary outcome, and changes in electroencephalographic signals and 1‐month data also were examined. Results: The BCI and PLC groups reported significant symptom reduction. The BCI group demonstrated larger effect size differences from the WLC group than the PLC group (mean change score: BCI vs. WLC, −2.60 vs. 0.38; 95% confidence interval, −3.67, −1.46 [p =.000; effect size, 1.07]; PLC, −2.26; 95% confidence interval, −3.33, −1.19 [p =.001 vs. WLC; effect size, 0.9]). At 1 month, symptoms continued to improve only for the BCI group. Targeted brain changes at the end of treatment predicted symptoms at 1 month for the BCI group only. Conclusions: BCI is a promising treatment for CIPN and may have a longer lasting effect than placebo (nonspecific BCI), which is an important consideration for long‐term symptom relief. Although scientifically interesting, the ability to separate real from placebo treatment may not be as important as understanding the placebo effects differently from effects of the intervention. Plain Language Summary: Chemotherapy‐induced nerve pain (neuropathy) can be disabling for cancer survivors; however, the way symptoms are felt depends on how the brain interprets the signals from nerves in the body.We determined that the perception of neuropathy can be changed by working directly with the brain.Survivors in our trial played 20 sessions of a type of video game that was designed to change the way the brain processed sensation and movement.In this, our second trial, we again observed significant improvement in symptoms that lasted after the treatment was complete. The current results demonstrated that a brain–computer interface was an effective treatment for chemotherapy‐induced peripheral neuropathy, with benefits maintained at the 1‐month follow‐up. Although scientifically interesting, the ability to separate real from placebo treatment may not be clinically helpful to obtain longer term significant relief for cancer survivors. [ABSTRACT FROM AUTHOR]

Pressure sensor-impregnated walkways transform a person's footfalls into spatiotemporal signals that may be sufficiently complex to inform emerging artificial intelligence (AI) applications in healthcare. Key consistencies within these plantar signals show potential to uniquely identify a person, and to distinguish groups with and without neuromotor pathology. Evidence shows that plantar pressure distributions are altered in aging and diabetic peripheral neuropathy, but less is known about pressure dynamics in chemotherapy-induced peripheral neuropathy (CIPN), a condition leading to falls in cancer survivors. Studying pressure dynamics longitudinally as people develop CIPN will require a composite model that can accurately characterize a survivor's gait consistencies before chemotherapy, even in the presence of normal step-to-step variation. In this paper, we present a state-of-the-art data-driven learning technique to identify consistencies in an individual's plantar pressure dynamics. We apply this technique to a database of steps taken by each of 16 women before they begin a new course of neurotoxic chemotherapy for breast or gynecologic cancer. After extracting gait features by decomposing spatiotemporal plantar pressure data into low-rank dynamic modes characterized by three features: frequency, a decay rate, and an initial condition, we employ a machine-learning model to identify consistencies in each survivor's walking pattern using the centroids for each feature. In this sample, our approach is at least 86% accurate for identifying the correct individual using their pressure dynamics, whether using the right or left foot, or data from trials walked at usual or fast speeds. In future work, we suggest that persistent deviation from a survivor's pre-chemotherapy step consistencies could be used to automate the identification of peripheral neuropathy and other chemotherapy side effects that impact mobility. [ABSTRACT FROM AUTHOR]

Background: Peripheral neuropathy predisposes to diabetic foot and this predilection is worsened by poorly controlled sugars. Diabetic foot increases the mortality and morbidity associated with diabetes. Thus, it is crucial to screen for diabetic polyneuropathy. Early detection of diabetic polyneuropathy improves foot care and decreases morbidity. This study aimed to assess the sensitivity of Semmes Weinstein monofilament test in the diagnosis of Diabetic Peripheral Neuropathy. Forty-three Type 2 diabetes mellitus patients availing IP/OP services of a Medical College Hospital were included for the study. Patients underwent Semmes Weinstein monofilament test, following which they were subjected to nerve conduction study of both lower limbs. Results: Forty six and half percentage of patients had diabetic peripheral neuropathy, taking NCS as gold standard.Of these 80% of the cases were also detected by the monofilament test.The specificity of the monofilament test was 100%. Positive predictive value was 100% and negative predictive value was 85.19% and the overall accuracy of the test was 90.7%. Conclusions: In this study, we found that sensitivity and specificity of the SWM test are fairly high; thus, it can be used as a valid screening tool for DPN in resource limited settings, such as India. [ABSTRACT FROM AUTHOR]

Introduction: Vincristine is used in many therapeutic schemes of oncological treatment in children, and one of its common complications is neurotoxicity. The aim of this study was to assess the incidence of vincristine-induced polyneuropathy in children treated for acute lymphoblastic leukemia. Secondly, we evaluated the clinical spectrum of chemotherapy-induced peripheral neuropathy. Material and methods: The study included 29 patients with newly diagnosed acute lymphoblastic leukemia who were treated according to the ALL IC-BFM 2009 therapeutic program. The study was designed for the induction remission phase, in which patients received unified anticancer treatment. A neurological assessment was performed on days 1, 8, 15, 22, 29 and 36 of treatment, and consisted of an original questionnaire completed by patients or their caregivers, a physical examination, and a neurological examination. Abnormalities were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0 scale. Results: Symptoms of polyneuropathy occurred in 25 patients (86.2%). Motor neuropathy was the most common type of polyneuropathy in the examined group. In half of the cases, the polyneuropathy was severe, rated at 3 or 4 points. The most serious course manifested itself in three patients in severe gastrointestinal ileus with subsequent intestinal perforation. In another case, rated at 4 points, breathing disorders occurred with apnea episodes. Conclusions: Vincristine-induced polyneuropathy is common in children with acute lymphoblastic leukemia in the induction of remission phase, and is severe in half of cases. In the pediatric population, in contrast to adults, vincristine- -induced polyneuropathy motor symptoms are predominant. [ABSTRACT FROM AUTHOR]

Background. Peripheral neuropathy is prevalent among patients with chronic kidney disease (CKD). Sudoscan non-invasively detects polyneuropathy by measuring electrochemical skin conductance (ESC). We conducted a study on sudomotor function in CKD patients across various stages based on their estimated glomerular filtration rate (eGFR). Methods. In this cross-sectional study of 700 CKD patients, all underwent Sudoscan. Pathological ESC was defined as hands < 40 μS or feet < 50 μS. Clinical neuropathy scores including Michigan Neuropathy Screening Instrument (MNSI) and Douleur Neuropathique en 4 questionnaire (DN4) were obtained. Results. Among participants, 344 had diabetes and 356 did not. Hands and feet ESC decreased with CKD progression (median (IQR) in stage 1–2, 3, 4–5: 54.0 (39.0–68.0), 45.5 (30.0–63.0), 41.8 (26.5–60.5), p trend < 0.001; 64.5 (53.5–74.0), 60.5 (43.0–72.5), 55.0 (39.0–69.8), p trend < 0.001). Pathological hands and feet ESC increased in later CKD stages (stage 1–2, 3, 4–5: 26.6%, 40.9%, 45.7%, p trend < 0.001; 21.7%, 34.0%, 40.6%, p trend < 0.001). Positive hands and feet ESC-eGFR correlation existed irrespective of diabetes. Diabetic patients had lower hands and feet ESC than non-diabetics as CKD progressed. However, multivariate regression found no significant ESC-eGFR association. Sudoscan correlated with clinical neuropathy scores. Conclusion. Pathological sudomotor function was common in non-dialysis CKD stages 4–5. Diabetic patients had worse function. Sudomotor dysfunction progressed with renal disease but eGFR was not an independent risk factor. [ABSTRACT FROM AUTHOR]

In the context of burn injury, growth factors (GFs) play a significant role in mediating the complex local and systematic processes that occur. Among the many systemic complications that arise following a burn injury, peripheral neuropathy remains one of the most common. Despite the broad understanding of the effects GFs have on multiple tissues, their potential implications in both wound healing and neuropathy remain largely unexplored. Therefore, this review aims to investigate the expression patterns of GFs prominent during the burn wound healing process and explore the potential contributions these GFs have on the development of burn-related peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Background/Importance: Dietary interventions, vitamins, and nutritional supplementation are playing an increasingly important role in the management of neuropathic pain. Current pharmacological treatments are poorly tolerated and ineffective in many cases. Objective: This systematic review aims to study the efficacy of dietary interventions, vitamins, and nutritional supplementation in the management of chronic neuropathic pain in adults. Evidence Review: The review followed PRISMA guidelines and was registered with PROSPERO (#CRD42022300312). Ten databases and gray literature, including Embase.com, MEDLINE and Web of Science, were systematically searched using a combination of keywords and controlled vocabulary related to chronic neuropathic pain and oral non‐pharmacological supplements. Studies on adult humans published between 2000 and 2021 were considered for inclusion. The Cochrane Handbook was used to assess risk of bias, and Grading of Recommendations Assessment, Development, and Evaluation was used to determine overall quality of evidence. Findings: Forty studies were included in the final review, and results were categorized according to pain type including pain related to chemotherapy‐induced peripheral neuropathy (CIPN, 22 studies, including 3 prospective cohorts), diabetic peripheral neuropathy (DPN, 13 studies, including 2 prospective), complex regional pain syndrome (CRPS‐I, 3 studies, including 1 prospective), and other (2 studies, both RCT). The CIPN studies used various interventions including goshajinkigan (4 studies), vitamin E (5), vitamin B12 (3), glutamine (3), N‐acetyl‐cysteine (2), acetyl‐l‐carnitine (2), guilongtonluofang (1), ninjin'yoeito (1), alpha‐lipoic acid (1), l‐carnosine (1), magnesium and calcium (1), crocin (1), and antioxidants (1), with some studies involving multiple interventions. All CIPN studies involved varying cancers and/or chemotherapies, advising caution for generalizability of results. Interventions for DPN included alpha‐lipoic acid (5 studies), vitamin B12 (3), acetyl‐l‐carnitine (3), vitamin E (1), vitamin D (2), and a low‐fat plant‐based diet (1). Vitamin C was studied to treat CRPS‐I (3 studies, including 1 prospective). Magnesium (1) and St. John's wort (1) were studied for other or mixed neuropathologies. Conclusions: Based on the review, we cannot recommend any supplement use for the management of CIPN, although further research into N‐acetyl‐cysteine, l‐carnosine, crocin, and magnesium is warranted. Acetyl‐l‐carnitine was found to be likely ineffective or harmful. Alpha‐lipoic acid was not found effective. Studies with goshajinkigan, vitamin B12, vitamin E, and glutamine had conflicting results regarding efficacy, with one goshajinkigan study finding it harmful. Guilongtonluofang, ninjin'yoeito, and antioxidants showed various degrees of potential effectiveness. Regarding DPN, our review supports the use of alpha‐lipoic acid, acetyl‐l‐carnitine, and vitamin D. The early use of vitamin C prophylaxis for the development of CRPS‐I also seems promising. Further research is warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Aim: In this study, we intend to evaluate the occurrence of small fiber neuropathy in patients with irritable bowel syndrome (IBS). Background: Small fiber neuropathy (SFN) is a sensory neuropathy that results from the degeneration of small Aδ and unmyelinated C fibers. SFN manifests positive symptoms, such as tingling, burning, prickling, and aching, and negative symptoms, including numbness, tightness, and coldness. The SFN coexistence with other comorbidities (e.g., fibromyalgia, inflammatory bowel disease, celiac disease) has been reported in previous studies. Methods: We conducted a cross-sectional study to assess the coexistence of SFN and IBS. Forty-two IBS patients and forty-three healthy individuals were asked to complete the Michigan Neuropathy Screening Instrument (MNSI) questionnaire. Results greater than three (>3) were considered positive. Participants with positive MNSI questionnaire results were examined for any neuropathy signs according to the Utah Early Neuropathy Scale (UENS) examination. The participants with positive results for the questionnaire and examination were checked for the sural and the superficial peroneal nerve conduction study (NCS). Normal NCS represented intact large fibers and the diagnosis of SFN. Results: Ten participants, 7 (16.7 %) in the IBS group and 3 (6.9 %) in the healthy group, had positive results for the questionnaire. Four participants were positive for the examination, with normal NCS, and were classified as SFN-positive. All four SFN diagnoses were from the IBS group. No one in the healthy group was diagnosed with SFN. We could find a significant statistical difference (p<0.05) between the IBS and healthy groups regarding the prevalence of SFN diagnosis. Conclusion: The co-occurrence of SFN and IBS suggests the possibility of a generalized neuropathy syndrome characterized by widespread neuronal impairment. Thus, any peripheral neuropathy symptom in IBS patients (and potentially other chronic pain disorders) should be evaluated for SFN since timely diagnosis and proper treatment result in a better quality of life for the patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of various cancer chemotherapy treatments, often leading to dose reduction or treatment discontinuation. The lack of a comprehensive understanding of its underlying mechanisms has hindered the development of effective CIPN treatments. Recent investigations focusing on axon degeneration mechanisms have identified NMNAT2 and SARM1 as key mediators of injury-induced axonal degeneration. In this review, our objective is to examine various studies shedding light on the interplay between NMNAT2 and SARM1 proteins and their roles in the progression of CIPN. We discuss three main aspects of the NMNAT2/SARM1 interplay: (1) the balance between NMNAT2 and SARM1 and their direct impact on NAD+ synthesis at the cellular level and axonal translocation; (2) the regulation by NMNAT2 and SARM1 of crucial downstream players implicated in neuronal cell death; (3) the role of SARM1 in activating immune cells, potentially contributing to the development of neuroinflammation. Additionally, we review the existing literature that explores the involvement of NMNAT2 and SARM1 in CIPN development and provide a summary of information on available inhibitors as potential therapeutic options. Chemotherapy-induced peripheral neuropathy (CIPN) commonly arises as a side effect of diverse cancer chemotherapy treatments. This condition presents symptoms such as numbness, tingling, and altered sensation in patients, often accompanied by neuropathic pain. Pathologically, CIPN is characterized by an intensive "dying-back" axonopathy, starting at the intra-epidermal sensory innervations and advancing retrogradely. The lack of comprehensive understanding regarding its underlying mechanisms explains the absence of effective treatments for CIPN. Recent investigations into axon degeneration mechanisms have pinpointed nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and sterile alpha and TIR motif-containing 1 protein (SARM1) as pivotal mediators of injury-induced axonal degeneration. In this review, we aim to explore various studies shedding light on the interplay between NMNAT2 and SARM1 proteins and their roles in the progression of CIPN. [ABSTRACT FROM AUTHOR]

Levodopa‐carbidopa intestinal gel therapy (LCIG), an effective treatment for advanced Parkinson's disease, can cause peripheral neuropathy. We present a 39‐year‐old man with LCIG‐related neuropathy with de novo diabetes mellitus (DM), decreased vitamin B6 and folate levels, and elevated homocysteine levels that developed over 2 years of LCIG treatment. Physicians should assess levels of levodopa metabolism‐associated vitamins and monitor risk factors of peripheral neuropathy, such as DM, before and after LCIG initiation. [ABSTRACT FROM AUTHOR]

Introduction: Small fiber neuropathy [SFN] is a common peripheral neurologic disorder with a vast array of implicated etiologies. It has previously been proposed that some forms of immune-mediated small fiber neuropathy are driven by vasculitis, though antinuclear cytoplasmic antibodies [ANCA] antibodies have not commonly been reported in association with SFN, thus far. We present this case series to discuss the observation of a possible novel association between ANCA and SFN. Methods: This is a retrospective case series of 6 patients with SFN and ANCA positivity, with and without systemic manifestations. Patients included were diagnosed with SFN by skin biopsy or autonomic function testing and were seropositive for ANCA by ELISA. Results: Six patients are outlined, including 4 females and 2 males. Antigen specific antibodies were MPO alone in 4 cases, PR3 alone in 1 case and both MPO and PR3 in 1 case. Systemic vasculitis was noted in 2 patients. Five patients received immunosuppression. Three patients experienced partial improvement, while symptoms stabilized in 3 patients. Discussion: This is the first series of patients with suspected immune-mediated SFN and ANCA antibody positivity, raising the possibility of ANCA mediated isolated SFN. This is in contradistinction to the more typical ANCA-mediated peripheral neuropathy manifestations of mononeuropathy multiplex or axonal sensorimotor neuropathy. We cannot unequivocally prove ANCA-associated vasculitis [AAV] causality in these cases; however, the stabilization in SFN symptomatology and associated improvement in ANCA antibody titer, after AAV treatment, may be indicative of an association. [ABSTRACT FROM AUTHOR]

Introduction: Peripheral neuropathy is common in chronic kidney disease (CKD) and may be multifactorial in origin, resulting from uremia, hyperkalemia, and diabetes. Previous studies have suggested that magnesium plays a crucial role in chronic pain. Studies evaluating magnesium in neuropathy have demonstrated mixed results. Aims: To provide preliminary data on the effectiveness of transdermal magnesium in treating peripheral neuropathy related to CKD. Methods: Twenty participants with advanced CKD were enrolled from a major teaching hospital clinic in Sydney, Australia. Each participant was provided with a spray bottle containing magnesium chloride and instructed to apply five sprays to each limb affected by neuropathy daily for 12 weeks. Participants completed the Neuropathy Total Symptom Score-6 (NTSS-6) every 4 weeks during follow-up. Serum magnesium concentrations were measured at 4-week intervals. Results: Twenty participants were recruited, of which 14 completed the 12-week follow-up period. Mean age was 78.90 years, 80.00% were female and mean estimated glomerular filtration rate was 9.78 mL/min/1.73 m2. With intention to treat analysis (mean [95% confidence interval]), NTSS-6 was significantly reduced at weeks 8 (4.04 [2.43–5.65]) and 12 (4.26 [2.47–6.05]), compared with baseline (6.92 [5.29–8.55]), p < 0.05. Serum magnesium concentration did not change significantly during the study. Conclusion: This pilot study suggests that transdermal magnesium may be beneficial in reducing frequency and severity of peripheral neuropathic symptoms in patients with advanced CKD. Trial Registration: australianclinicaltrials.gov.au. Identifier: ACTRN12621000841875. Date first registered January 7, 2021. [ABSTRACT FROM AUTHOR]

A pilot study published in Obesity Surgery examined the presence of peripheral neuropathy (PN) and cardiovascular autonomic neuropathy (CAN) in individuals who had undergone Roux-en-Y gastric bypass (RYGB) surgery. The study found that individuals with prior RYGB surgery showed signs of neuropathy, and all participants had confirmed nutritional and/or metabolic deficiencies. The study suggests that larger studies are needed to confirm these findings in unselected cohorts. The article highlights the potential risks of micronutrient malabsorption and long-term nutritional deficiencies in patients who have undergone RYGB surgery. [Extracted from the article]

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side-effect resulting from numerous neurotoxic chemotherapies that damages the peripheral nerves, alters sensations in the hands and feet, causes burning and shooting pains, and impairs a patient's quality of life (QoL). There are limited established interventions to help improve CIPN symptoms. There is only one pharmacological agent (Duloxetine) for treatment of CIPN; however, it only has mild benefit, signaling a critical need for alternative management options to manage patient symptoms. Multiple studies suggest therapeutic benefits of exercise in cancer care to improve physical and psychological functioning; however, the benefits regarding CIPN symptoms and physical function are less clear. This narrative review synthesizes research articles investigating the effect and mechanisms induced by different exercise programs for patients with taxane-induced peripheral neuropathy (TIPN) symptoms and function. The overall incidence, manifestations, characteristics, and mechanisms of CIPN are also discussed. While some studies in this narrative review demonstrated that exercise programs may have benefits on sensory and motor TIPN symptoms in some but not all patients, there are consistent benefits of improved QoL and physical function across most patients. This narrative review highlights the need for future research to confirm the effects of exercise for TIPN, with a focus on other important components, including the effect of exercise adherence, type, and supervision level. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study is to describe the ultrasound (US) and magnetic resonance imaging (MRI) findings in patients with neuropathies affecting the deep (DB) and superficial (SB) branches of the Ulnar nerve (UN) and to investigate the potential role of imaging modalities in the diagnostic workup of these conditions. Materials and methods: We screened our institutional imaging database to identify patients with a diagnosis of UN mononeuropathy, and among them, we reviewed the cases where US disclosed pathological findings affecting the UN terminal divisions. In this latter subgroup, we retrieved available data on MRI and electrodiagnostic tests performed by the patients during the diagnostic workup. All the patients were evaluated with US machines equipped with 17–5-MHz, 18–4-MHz, 24–8-MHz, or 22–8-MHz probes. MRI exams were performed on a 3-T unit equipped with a 64-channel head RF coil. Results: Among 166 patients with UN mononeuropathy, we retrieved 15 patients (9%) for which US detected pathological findings affecting the UN terminal divisions, consisting of 7 cases of DB neuropathy, 4 cases of SB neuropathy, and 4 cases of combined neuropathy involving both nerves. Seven (46.7%) patients were submitted to MRI to integrate US findings. Among patients with SB and DB neuropathies, imaging allowed the identification of 7 traumatic nerve injuries, 2 nerve tumors, and 6 entrapment neuropathies, including 4 cases of nerve compression by a ganglion cyst. Conclusion: High-resolution US and MRI are accurate modalities for the investigation of patients with SB/DB neuropathy, can provide critical information on the cause of nerve damage, and guide therapeutic decisions. Critical relevance statement: High-resolution US and MRI are accurate modalities for the investigation of patients with superficial/deep branch of the ulnar nerve neuropathy. In the proper setting, US may be regarded as a first-line approach in patients with suspected neuropathies affecting these small branches. Key points: • Neuropathies affecting the distal ulnar nerve often require multimodal investigations. • US and MRI can provide detailed morphological information about the terminal branches of the ulnar nerve. • US may be considered as a first-line approach in suspected distal ulnar nerve neuropathies. [ABSTRACT FROM AUTHOR]

Background: Anti-Hu antibody neuropathy is considered a rare acquired peripheral neuropathy, but common among paraneoplastic syndromes. Typically, is described as subacute sensory neuronopathy and electrophysiological findings are usually suggestive of a sensory axonal neuropathy. Case presentation: We report the case of a 67-year-old man referred to our clinic with a 4-month history of progressive pain and paresthesias of distal lower limbs. He had a 30-year history of alcohol abuse and smoking. Alcoholic neuropathy was considered the most likely diagnosis, considering his history and evaluation. The patient's neurological examination revealed symmetric bilateral superficial and deep sensory loss in the lower extremities, reduced Achilles tendon reflexes and wide based gait. Electrophysiological testing was suggestive of axonal sensory-motor polyneuropathy and small fiber involvement. Even though alcohol consumption was discontinued, symptoms gradually worsened. Further testing was performed and the patient was found seropositive for anti-Hu antibody. Small-cell lung cancer was detected later, but patient passed away before treatment for cancer was administrated. Conclusions: The aim of our paper is to report a case of a rare paraneoplastic syndrome that can cause progressive sensory-motor neuropathy with large and small fiber involvement, which should be rapidly differentially diagnosed from other neuropathies, so that the underlying cause can be identified and, potentially, treated. [ABSTRACT FROM AUTHOR]

Background Gaucher disease (GD) is an autosomal recessive disease characterized by an inborn metabolic error. Although pain attributed to skeletal involvement is one of the most frequent symptoms of this condition, some patients may have neuropathic pain. Therefore, recent studies have analyzed the occurrence of peripheral polyneuropathy in patients with GD. In these studies, in cases when normal neurological examination and electroneuromyography were found, small fiber neuropathy (SFN) was investigated, mainly using skin biopsy and quantitative sensory testing. Case presentation We demonstrate the usefulness of the skin-wrinkling test performed by immersion in water for the evaluation of SFN in a 27-year-old woman with GD who presented with neuropathic pain. After excluding other causes, the main hypothesis was an association between SFN and GD, which was recently described in the literature and possibly underdiagnosed. Conclusions Although only skin biopsy can confirm the diagnosis of SFN, the skin-wrinkling test can be useful for the complimentary assessment of pain in patients with GD, owing to its easy application and wide availability. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting side effect of systemic cancer therapy. In many cancer survivors, CIPN persists after treatment ends and is associated with functional impairments, abnormal gait patterns, falls, and diminished quality of life. However, little is known regarding which patients are most likely to develop CIPN symptoms that impair mobility and increase fall risk, when this risk develops, or the optimal timing of early intervention efforts to mitigate the impact of CIPN on functioning and fall risk. This study will address these knowledge gaps by (1) characterizing trajectories of symptoms, functioning, and falls before, during, and after treatment in adults prescribed neurotoxic chemotherapy for cancer; and (2) determining the simplest set of predictors for identifying individuals at risk for CIPN-related functional decline and falls. Methods: We will enroll 200 participants into a prospective, observational study before initiating chemotherapy and up to 1 year after completing chemotherapy. Eligible participants are aged 40–85 years, diagnosed with stage I-III cancer, and scheduled to receive neurotoxic chemotherapy. We perform objective assessments of vibratory and touch sensation (biothesiometry, tuning fork, monofilament tests), standing and dynamic balance (quiet stance, Timed-Up-and-Go tests), and upper and lower extremity strength (handgrip dynamometry, 5-time repeated chair stand test) in the clinic at baseline, every 4–6 weeks during chemotherapy, and quarterly for 1 year post-chemotherapy. Participants wear devices that passively and continuously measure daily gait quality and physical activity for 1 week after each objective assessment and self-report symptoms (CIPN, insomnia, fatigue, dizziness, pain, cognition, anxiety, and depressive symptoms) and falls via weekly electronic surveys. We will use structural equation modeling, including growth mixture modeling, to examine patterns in trajectories of changes in symptoms, functioning, and falls associated with neurotoxic chemotherapy and then search for distinct risk profiles for CIPN. Discussion: Identifying simple, early predictors of functional decline and fall risk in adults with cancer receiving neurotoxic chemotherapy will help identify individuals who would benefit from early and targeted interventions to prevent CIPN-related falls and disability. Trial registration: This study was retrospectively registered with ClinicalTrials.gov (NCT05790538) on 3/30/2023. [ABSTRACT FROM AUTHOR]

Diabetic neuropathies are the most frequent complications of diabetes, contributing to high morbidity, excess mortality, reduced quality of life, and increased healthcare costs. Prediabetes is characterised by glucose levels within an intermediate range above normoglycaemia yet below the diagnostic threshold for diabetes. In 2021, 10.6% and 6.2% of adults worldwide were estimated to have impaired glucose tolerance and impaired fasting glucose, respectively, the majority of whom are unaware of having prediabetes. Evidence has accumulated suggesting that prediabetes is a predictor of cardiovascular disease (CVD) and increased mortality. The past 2 decades have witnessed an extensive debate, particularly among diabetologists and neurologists, as to whether prediabetes is associated with peripheral neuropathy. In this review, we elaborate on the current evidence, particularly from population‐based studies supporting an increased risk of distal sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN) in people with prediabetes. Moreover, we discuss whether lifestyle interventions showing efficacy in preventing or delaying the transition from prediabetes to diabetes in persons with prediabetes may also exert favourable effects on the development and progression of DSPN and CAN. This review should help in raising the awareness of and translating the current knowledge on neuropathies in people with prediabetes into clinical practice and public health. The current recommendation that adults who are overweight or obese should be screened for prediabetes and referred to or offered preventive interventions should ultimately culminate in preventing not only CVD but also prediabetic neuropathy. [ABSTRACT FROM AUTHOR]

Valid, responsive blood biomarkers specific to peripheral nerve damage would improve management of peripheral nervous system (PNS) diseases. Neurofilament light chain (NfL) is sensitive for detecting axonal pathology but is not specific to PNS damage, as it is expressed throughout the PNS and CNS. Peripherin, another intermediate filament protein, is almost exclusively expressed in peripheral nerve axons. We postulated that peripherin would be a promising blood biomarker of PNS axonal damage. We demonstrated that peripherin is distributed in sciatic nerve, and to a lesser extent spinal cord tissue lysates, but not in brain or extra-neural tissues. In the spinal cord, anti-peripherin antibody bound only to the primary cells of the periphery (anterior horn cells, motor axons and primary afferent sensory axons). In vitro models of antibody-mediated axonal and demyelinating nerve injury showed marked elevation of peripherin levels only in axonal damage and only a minimal rise in demyelination. We developed an immunoassay using single molecule array technology for the detection of serum peripherin as a biomarker for PNS axonal damage. We examined longitudinal serum peripherin and NfL concentrations in individuals with Guillain-Barré syndrome (GBS, n = 45, 179 time points), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 35, 70 time points), multiple sclerosis (n = 30), dementia (as non-inflammatory CNS controls, n = 30) and healthy individuals (n = 24). Peak peripherin levels were higher in GBS than all other groups (median 18.75 pg/ml versus < 6.98 pg/ml, P < 0.0001). Peak NfL was highest in GBS (median 220.8 pg/ml) and lowest in healthy controls (median 5.6 pg/ml), but NfL did not distinguish between CIDP (17.3 pg/ml), multiple sclerosis (21.5 pg/ml) and dementia (29.9 pg/ml). While peak NfL levels were higher with older age (rho = +0.39, P < 0.0001), peak peripherin levels did not vary with age. In GBS, local regression analysis of serial peripherin in the majority of individuals with three or more time points of data (16/25) displayed a rise-and-fall pattern with the highest value within the first week of initial assessment. Similar analysis of serial NfL concentrations showed a later peak at 16 days. Group analysis of serum peripherin and NfL levels in GBS and CIDP patients were not significantly associated with clinical data, but in some individuals with GBS, peripherin levels appeared to better reflect clinical outcome measure improvement. Serum peripherin is a promising new, dynamic and specific biomarker of acute PNS axonal damage. [ABSTRACT FROM AUTHOR]

Background: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting toxicity that markedly limits the use of oxaliplatin and affects quality of life. Statins have been shown to exert neuroprotective effects in preclinical settings. The aim of the present study was to clarify whether statins prevented OIPN in patients with colorectal cancer (CRC) receiving adjuvant CAPOX therapy. Methods: We examined 224 patients who received adjuvant CAPOX therapy for CRC between July 2010 and December 2021 at our hospital. Patients were divided into "Statin" and "Non-statin" groups based on statin use. Details on and the adverse events of adjuvant CAPOX therapy were examined in association with statin use. Results: Thirty-one patients (14%) were treated with statins. There were no intergroup differences in the relative dose intensity or number of CAPOX cycles between the Statin and Non-statin groups. In total, 94% of patients in the Statin group and 95% of those in the Non-statin group developed OIPN (p=0.67). The severity of OIPN was similar between the two groups (p=0.89). The frequency of treatment delays in CAPOX did not significantly differ between the Statin and Non-statin groups (16% vs. 11%, p=0.45). Conclusions: The efficacy of statins to attenuate OIPN during adjuvant CAPOX therapy was not apparent in the current study. Further studies are needed to confirm the present results. [ABSTRACT FROM AUTHOR]

Appropriate animal models, mimicking conditions of both health and disease, are needed to understand not only the biology and the physiology of neurons and other cells under normal conditions but also under stress conditions, like nerve injuries and neuropathy. In such conditions, understanding how genes and different factors are activated through the well-orchestrated programs in neurons and other related cells is crucial. Knowledge about key players associated with nerve regeneration intended for axonal outgrowth, migration of Schwann cells with respect to suitable substrates, invasion of macrophages, appropriate conditioning of extracellular matrix, activation of fibroblasts, formation of endothelial cells and blood vessels, and activation of other players in healthy and diabetic conditions is relevant. Appropriate physical and chemical attractions and repulsions are needed for an optimal and directed regeneration and are investigated in various nerve injury and repair/reconstruction models using healthy and diabetic rat models with relevant blood glucose levels. Understanding dynamic processes constantly occurring in neuropathies, like diabetic neuropathy, with concomitant degeneration and regeneration, requires advanced technology and bioinformatics for an integrated view of the behavior of different cell types based on genomics, transcriptomics, proteomics, and imaging at different visualization levels. Single-cell-transcriptional profile analysis of different cells may reveal any heterogeneity among key players in peripheral nerves in health and disease. [ABSTRACT FROM AUTHOR]

Cannabigerol (CBG), derived from the cannabis plant, acts as an acute analgesic in a model of cisplatin-induced peripheral neuropathy (CIPN) in mice. There are no curative, long-lasting treatments for CIPN available to humans. We investigated the ability of chronic CBG to alleviate mechanical hypersensitivity due to CIPN in mice by measuring responses to 7 and 14 days of daily CBG. We found that CBG treatment (i.p.) for 7 and 14 consecutive days significantly reduced mechanical hypersensitivity in male and female mice with CIPN and reduced pain sensitivity up to 60–70% of baseline levels (p < 0.001 for all), 24 h after the last injection. Additionally, we found that daily treatment with CBG did not evoke tolerance and did not incur significant weight change or adverse events. The efficacy of CBG was independent of the estrous cycle phase. Therefore, chronic CBG administration can provide at least 24 h of antinociceptive effect in mice. These findings support the study of CBG as a long-lasting neuropathic pain therapy, which acts without tolerance in both males and females. [ABSTRACT FROM AUTHOR]

Purpose: Subclinical inflammation may be involved in the pathogenesis of diabetic cardiac autonomic neuropathy (DCAN). The purpose of the study is to explore the relationship between novel inflammation biomarkers fibrinogen-albumin ratio (FAR), fibrinogen-prealbumin ratio (FPR), and DCAN in type 2 diabetes mellitus (T2DM).Patients and Methods: A total of 715 T2DM patients were enrolled in this retrospective study, divided into non-DCAN (n=565) and DCAN (n=150) groups by Ewing's test. Serum fibrinogen, albumin, prealbumin, routine inflammatory and other biochemical markers were measured.Results: Patients with versus without DCAN had higher FAR (10.29 ± 4.83 vs 7.22 ± 2.56 g/g, P < 0.001) and FPR (2.19 ± 1.85 vs 1.43 ± 0.93 g/mg, P < 0.001). As FAR and FPR quartiles increased, the incidence of DCAN increased (Quartile 1 vs Quartile 4: 8.4 vs 42.7%, 9.6 vs 39.2%, respectively, P < 0.001), heart rate variability parameters decreased (P < 0.001); the incidence of diabetic nephropathy, retinopathy and peripheral neuropathy tended to be higher and inflammation factors were more active (P < 0.01). FAR (OR, 95% CI: 1.16, 1.08– 1.25, P < 0.001) and FPR (OR, 95% CI: 1.22, 1.03– 1.44, P = 0.021) were independent determinants of DCAN; the risk of DCAN increased by approximately 65% and 27% with each increase in the standard deviation (SD) of FAR (OR per SD, 95% CI: 1.65, 1.29– 2.11, P < 0.001) and FPR (OR per SD, 95% CI: 1.27, 1.04– 1.56, P = 0.021).Conclusion: FAR and FPR are independent risk factors and may influence DCAN development through inflammation. [ABSTRACT FROM AUTHOR]