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Abstract Background: Dietary copper intake is a promising predictor of peripheral neuropathy. There is no research exploring the potential link between dietary copper intake and peripheral neuropathy. Methods: The information utilized in our research was collected from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004. The relationship between dietary copper intake and peripheral neuropathy was analyzed using a multivariate logistic regression model and restricted cubic spline (RCS). Results: The RCS analysis results showed a U-shaped nonlinear relationship between dietary copper intake and peripheral neuropathy (P for nonlinearity

Abstract Background Paclitaxel-induced peripheral neuropathy (PIPN) is one of the most common and debilitating toxicity. Up till now, no treatment or preventive medication is recommended by guidelines. Pentoxifylline has been found to prevent PIPN in animal models. This study aimed to evaluate the tolerability and efficacy of pentoxifylline in preventing PIPN. To our knowledge, this is the first clinical trial to evaluate the potential effect of pentoxifylline on the prevention of PIPN in breast cancer (BC) patients. Results A simple-randomized placebo-controlled study was conducted on 60 BC patients receiving weekly paclitaxel and either pentoxifylline 400 mg twice daily (n = 30) or placebo (n = 30) for 12 weeks. Only 55 patients completed the study. The main objective was the evaluation of the effect of pentoxifylline on the incidence of PIPN which revealed no significant difference between the pentoxifylline group (85%) and the placebo group (100%). Secondary objectives included time to develop grade 2 or 3 (TTG 2/3) PIPN, the patient’s quality of life (QOL), serum tumor necrosis factor-α (TNF-α) and malondialdehyde and the tolerability of pentoxifylline. The median TTG 2/3 PIPN was not reached in the pentoxifylline group compared to 77 days (95% confidence interval of 70.91 to 83.07) in the placebo group. However, the difference did not reach significance. The assessment of the impact of PIPN on QOL was performed at baseline and at weeks 4, 8 and 12 using Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) subscale. The magnitude of the worsening in the QOL was significantly lower in the pentoxifylline group than in the placebo group at weeks 4, 8, and 12 (p values = 0.028, 0.003, and 0.018, respectively). Analysis of the serum TNF-α and malondialdehyde revealed no significant differences between the groups. Pentoxifylline was safe, tolerable and did not affect paclitaxel toxicity. Conclusion Oral pentoxifylline (400 mg twice daily) did not decrease the incidence of PIPN. However, it improved patients’ QOL significantly. Trial registration Clinical Trials.gov, NCT05189535. Registered 4 October 2021, https://classic.clinicaltrials.gov/ct2/show/NCT05189535 .

Abstract Background Bartonella species are fastidious, intracellular bacteria responsible for an expanding array of human pathologies. Most are considered to be transmitted by direct inoculation with infected bodily fluids from a mammalian reservoir species or vector-transmitted through a variety of arthropod species and their excrement. However, there are mounting reports of infection in the absence of documented animal or vector contact. A variety of Bartonella species have been documented in conditions affecting both the peripheral and central nervous systems. More common conditions, including neuroretinitis, are often associated with Bartonella henselae. However, Bartonella quintana, the agent of trench fever, as well as emerging pathogens related to rodent reservoir species, B. grahamii and B. elizabethae, have also been documented. Encephalitis and encephalopathy, also most often associated with B. henselae, have been reported with B. quintana, B. washoensis (ground squirrels) and B. vinsonii subsp. vinsonii (voles) infections. Bartonella infections have also been associated with peripheral neuropathies, such as cranial nerve paresis and neuropathic pain, including infection with less commonly encountered species such as Bartonella koehlerae. Recently, molecular diagnostic testing revealed that DNA from Bartonella spp. was found to be more prevalent in blood of patients with neuropsychiatric disorders such as schizophrenia and psychoses compared to healthy controls. Methods A systematic literature search was conducted on PubMed, Google Scholar and Web of Science. Search terms included Bartonella and specific neurological conditions and focused on peer-reviewed case reports published after 2012 pursuant to a prior review, with limited exceptions for conditions not previously covered. Published diagnostic testing, serology, molecular testing or pathology, were necessary for inclusion, except for one case which had clinical and epidemiological evidence consistent with diagnosis along with follow-up. Results Neurobartonelloses included neuralgic amyotrophy, complex regional pain syndrome, chronic inflammatory demyelinating polyneuropathy, cranial nerve paralysis, Guillain-Barré syndrome, peripheral vasculitic polyneuropathy, acute transverse myelopathy, neuroretinitis, encephalitis/encephalopathy, cerebral vasculitis/aneurysm and neuropsychiatric conditions. Conclusions The breadth of reported symptoms and clinical syndromes associated with an increasing number of Bartonella species continues to expand. Increased clinical awareness of this important zoonotic pathogen is necessary to advance One Health among the medical and veterinary communities. Graphical Abstract

OBJECTIVE: This Study aimed to determine the frequency of sensory neuropathy in the feet of asymptomatic people with type II diabetes mellitus. METHODOLOGY: This cross-sectional Study was conducted at the medical department of MTI/Lady Reading Hospital, Peshawar, between April - October 2022. A total of 133 patients were observed using a non-probability consecutive sampling technique. Patients aged 25-60 years who had type II diabetes mellitus for more than one year were included, while patients with vitamin B12 deficiency who used multivitamins were excluded from the study. SPSS version 20 was used for statistical analysis. RESULTS: Age-wise distribution 25-30 Years (4.5%), 31-40 Years (21.8%), 41-50 Years (45.9%), and 51-60 Years (27.8%) (mean 45.56±3.3). Gender-wise, 104 (78.2%) were male and 29 (21.8%) were female. Regarding education level, 57 (42.9%) were illiterate, 46 (34.6%) had secondary education, and 30 (22.6%) had higher education. Residency status indicated 105 (78.9%) from urban areas and 28 (21.1%) from rural areas. Socioeconomic status was distributed as follows: 53 (39.8%) with a monthly income >100,000 Rs, 46 (34.6%) with an income range of 50,000 to 100,000 Rs, and 34 (25.6%) with an income range

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 Background Peripheral neuropathy (PN) is a common neurological complication of HIV (Human Immunodeficiency Virus) that can significantly affect patients’ quality of life. In Ethiopia, children living with HIV are at an increased risk of developing peripheral neuropathy due to comorbidities such as anemia, tuberculosis, malnutrition, and poor socio-economic status. Our study aims to evaluate the prevalence of peripheral neuropathy among children living with HIV in Ethiopia using a simple clinical screening tool. Methods A health institution-based cross-sectional study was conducted among 148 children aged 5 to 18 years living with HIV who are receiving treatment at the antiretroviral therapy (ART) clinic of the randomly selected public health institutions in the Gamo zone. An interview and neurologic examination were conducted. A binary logistic regression model was used to identify factors associated with the outcome variable. Variables with p-value

Abstract Antibody–drug conjugates (ADCs) are among the fastest-growing classes of anticancer drugs, making it crucial to evaluate their potential for causing peripheral neuropathy. We analyzed data from the FAERS database (January 1, 2014, to June 30, 2023) using disproportionality and Bayesian methods. We identified 3076 cases of ADC-associated peripheral neuropathy. Our study revealed significant signals for all ADCs (ROR 1.82, 95% CI 1.76–1.89). ADCs with tubulin-binding payloads showed significant peripheral neuropathy signals (ROR 2.31, 95% CI 2.23–2.40), whereas those with DNA-targeting (ROR 0.48, 95% CI 0.39–0.59) and topoisomerase 1 inhibitor (ROR 0.56, 95% CI 0.48–0.66) payloads exhibited non-significant signals. Signals for peripheral sensory neuropathy were 4.83, 2.44, 2.74, and 2.21 (calculated based on IC025) for brentuximab vedotin, trastuzumab emtansine, enfortumab vedotin, and polatuzumab vedotin, while signals for peripheral motor neuropathy were 5.31, 0.34, 2.27, and 0.03, respectively. The median time to onset for all ADCs was 127 days (interquartile range 40–457). Tisotumab vedotin had the highest hospitalization rate at 26.67%, followed by brentuximab vedotin at 25.5%. Trastuzumab emtansine had the highest mortality rate ,with 80 deaths (11.96%) among 669 cases. Based on FAERS database, only ADCs with tubulin-binding payloads exhibited significant peripheral neuropathy signals. Brentuximab vedotin and enfortumab vedotin showed similar profiles for peripheral sensory neuropathy and motor neuropathy. Given the delayed time to onset and potentially poor outcomes, ADC-related peripheral neuropathy warrants significant attention.

Abstract Background Cortical auditory evoked potentials (CAEPs) display both auditory processing and neurological activity in the auditory cortex. The purpose of this research is to evaluate the importance of CAEPs in identifying auditory processing disorders in patients with peripheral neuropathy (PN) in different pathologies. Sixty cases with PN of different pathologies represented the study group which was classified into two subgroups according to the underlying pathology of PN: those with either axonal PN (44 patients) and those with demyelinating PN (16 patients). The current study also included a control group of 40 healthy volunteers who did not have any peripheral or central auditory neurological disorders. CAEPs were recorded in both groups. Results The study group’s CAEP response showed significantly delayed latencies than the control groups. Comparing the two study subgroups revealed that the axonal PN group had significant delayed latencies of N1 and P2 components in comparison to the demyelinating PN group. Conclusion Cortical auditory evoked potentials can be used efficiently to diagnosis central auditory processing disorders in patients with PN. CAEP latencies can be employed alone or in conjunction with amplitudes; however, CAEP latencies are more significant than amplitudes for such purpose. Both demyelinating and axonal PN are associated with impaired auditory processing; however, axonal PN patients are more likely to be affected, suggesting that axonal PN has a significantly drastic effect on the central auditory nervous system.

Abstract Diabetic peripheral neuropathy is one of the diabetes most common microvascular complications. It is very prevalent in Sub-Saharan Africa due to a combination of causes, including rising diabetes prevalence, limited healthcare resources, and a lack of access to competent medical care. However, just a few studies have been undertaken in the study area. Institution-based cross-sectional study was conducted in the Amhara region referral hospitals, in 2022. By using a systematic random sampling technique, a total of 627 respondents were included. The data was entered into EPI Data version 4.6 and exported to SPSS version 25 for further analysis. A binary logistic regression was used to determine the relationship between the dependent and predictor variables. The association between predictor variables and the dependent variable was determined using multivariate logistic regression [p value

Yan-Jun Xiong,* Yu Xiao,* Lei Xie, Lei Gao, Yi Han, Peng-Fei Huang, Shuang Liu, Ya-Xue Liang, Hua Wang Department of Tuberculosis, Anhui Provincial Chest Hospital (Anhui Institute of Tuberculosis Control), Hefei, Anhui, 230022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hua Wang, Department of Tuberculosis, Anhui Provincial Chest Hospital (Anhui Institute of Tuberculosis Control), No. 392, Jixi Road, Hefei, Anhui, People’s Republic of China, Tel +86 13395694530, Email 1726553540@qq.comBackground: Linezolid (LZD) is a cornerstone medication in the treatment of drug-resistant tuberculosis (DR-TB). However, it frequently triggers adverse effects such as bone marrow suppression, optic neuropathy, and peripheral neuropathy, all of which can impact treatment outcomes and prognosis. Contezolid (CZD), a novel oxazolidinone antibiotic, exhibits comparable antimicrobial efficacy against Mycobacterium tuberculosis as LZD, but with potentially enhanced safety profiles.Case Presentation: This report presents five cases (Cases 1– 5) of LZD intolerance, wherein CZD served as an effective alternative treatment. In Cases 1– 3, LZD administration resulted in bone marrow suppression, primarily manifested as anemia. Transitioning to CZD therapy led to a rise and stabilization of hemoglobin (HGB) levels in Cases 1– 2, and a return to baseline values in Case 3. In Case 4, CZD treatment alleviated symptoms of LZD-induced peripheral neuritis, although complete resolution was not achieved, hinting at potential irreversibility of this type of peripheral neuropathy. In Case 5, direct CZD anti-TB therapy was initiated for recurrent leukopenia and neutropenia, resulting in no further severe myelosuppression and successful recovery.Conclusion: These case studies suggest that CZD could represent an effective and safe option for anti-TB therapy, especially for patients intolerant to LZD.Keywords: contezolid, linezolid, drug-resistant tuberculosis, myelosuppression, peripheral neuropathy

Lisha Sun,1,&ast; Xiaoran Zhang,1,&ast; Jiao Yang,1,&ast; Jun Yuan,2 Xingxing Lei1 1Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China; 2Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xingxing Lei, Email iopmj38169@tom.comObjective: Visceral fat area (VFA) levels have been found to exhibit a strong association with various conditions such as insulin resistance (IR), inflammation, oxidative stress, metabolic syndrome (MetS), hyperlipidemia, diabetes, and its vascular complications. These complications include hypertension, cardiovascular disease, diabetic retinopathy (DR), albuminuria, and cardiovascular autonomic dysfunction, which is considered one of the main types of diabetic neuropathy. This study aimed to investigate the correlation between visceral fat and peripheral neuropathy in patients with type 2 diabetes (T2DM).Methods: A retrospective analysis of clinical data of patients diagnosed with type 2 diabetes admitted to our hospital was conducted. After excluding 28 cases, a total of 488 patients were included, divided into the group with peripheral neuropathy (207 cases) and the control group without peripheral neuropathy (281 cases). The correlation between VFA and the presence of DPN was assessed using correlation and multiple logistic regression analyses.Results: In terms of general information, the group with peripheral neuropathy had lower BMI but longer duration of diabetes compared to the control group. Regarding biochemical indicators, VFA were lower in the group with peripheral neuropathy, while FPG and HbA1c levels were higher (all P< 0.05). Spearman correlation analysis showed a negative correlation between VFA, and the presence of peripheral neuropathy in patients with type 2 diabetes (P< 0.05). Logistic regression analysis indicated that VFA, duration of diabetes, and HbA1c level were influencing factors for the occurrence of peripheral neuropathy in patients with type 2 diabetes (P< 0.05).Conclusion: This study revealed a correlation between visceral fat and peripheral neuropathy in patients with type 2 diabetes, highlighting the importance of monitoring visceral fat in such patients. In addition to lower levels of VFA, factors such as duration of diabetes and glycated hemoglobin (HbA1c) level were also associated with peripheral neuropathy in patients with T2DM.Keywords: type 2 diabetes, visceral fat, peripheral neuropathy, correlation, metabolic complications

Objective: This cross-sectional study aimed to assess the perceived chemotherapy-induced peripheral neuropathy (CIPN) symptoms in patients with breast cancer who received taxane-based chemotherapy. Methods: A total of 74 patients with breast cancer who underwent taxane-based chemotherapy were screened and invited to participate in this study. Perceived symptoms of CIPN were assessed via the European Organization for Research and Treatment of Cancer-Chemotherapy Induced Peripheral Neuropathy (EORTC-CIPN20) questionnaire after the completion of systemic treatment within a month and a half. Sensory, motor, and autonomic subscale scores were calculated and analyzed for each patient. Results: This study included 52 patients with breast cancer. The mean total exposure dose was 2093.92±1266.22 mg. The rates of adjuvant and neoadjuvant chemotherapy were similar (n=25 vs. n=27). Most patients underwent breast-conserving surgery (65.4%). The types of chemotherapy regimen were combined anthracycline and paclitaxel (n=28), docetaxel (n=14), and combined anthracycline, pertuzumab, trastuzumab, and docetaxel (n=10). Patients who underwent modified radical mastectomy had significantly higher scores in the perceived symptoms of CIPN motor function subscale of EORTC-CIPN20 (z=-2.838, p=0.005). The autonomic subscale of EORTC-CIPN20 was significantly correlated with age (r=-0.373, p=0.006) and with the total exposure dose of chemotherapy (r=0.295, p=0.034). Conclusion: The type of surgery, specifically MRM, which has been emphasized as a contributing factor to CIPN, should be taken into consideration for further potential deterioration. By this means, it is reasonable to state that not only ongoing monitoring of the CIPN is of utmost importance, but also potential contributors to the management of the CIPN are of great importance.

Background: Bortezomib and dexamethasone (BD) regimen offers a promising therapeutic approach in multiple myeloma (MM) by inhibiting the proteolytic pathway of tumor cells. Aims and Objectives: This study aims to assess the safety profile and treatment outcomes of MM patients undergoing the BD regimen. Materials and Methods: This prospective observational study included MM patients who received BD regimen. Patients received bortezomib (1.3 mg/m2 intravenous) weekly for 4 weeks along with dexamethasone (40 mg orally) weekly for 4 weeks. Clinical assessments were performed after each cycle, and adverse drug reactions were graded according to National Cancer Institute criteria. Treatment outcomes were evaluated after the 4th cycle based on specific parameters. Results: Thirty-seven patients, with a mean age of 56.2 years, predominantly male (56.8%), were included. Common symptoms included bone pain, fatigue, weight loss, and appetite loss. Toxicities were mainly grade 1 and 2, with peripheral neuropathy (PN) being the most prevalent. The BD regimen exhibited a response rate of 65%, accompanied by significant improvements in bone marrow plasma cells, β2 microglobulin, immunoglobulin assay, and erythrocyte sedimentation rate. In addition, treatment improved performance status, in 51.4% of patients achieving scores above 90 on the Karnofsky scale. Conclusion: The BD regimen demonstrated notable efficacy and tolerability in MM treatment. However, it is associated with a higher risk of PN.

Highlight: • Chemotherapy induces neurotoxicity through DNA crosslink, impaired calcium homeostasis, mitochondrial damage, increased reactive oxygen species, pro-inflammatory cascade, axon degeneration, and programmed cell death. • CIPN has a primary impact on the sensory neuron. • CIPN is diagnosed based on the patient's history, chemotherapy history, and neurologic examination. Some pharmacological and non-pharmacological treatments are hypothesized to reduce CIPN symptoms, but only duloxetine is recommended. ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is the most common and severe neurological side effect of many commonly used chemotherapy agents. It affects more than 60% of cancer patients. Approximately 30%–40% of patients have persistent symptoms five months or longer after stopping treatment. Even years after completing chemotherapy, some patients still experience CIPN symptoms. CIPN increases the annual cost of healthcare, leads to detrimental dose reduction and even cessation of treatment, and severely affects cancer survivors’ quality of life. Chemotherapy induces neurotoxicity through a variety of mechanisms that lead to neuronal cell damage or cell death. This mechanism of neurotoxicity varies depending on the specific agent. CIPN is characterized predominantly by sensory axonal peripheral neuropathy. Motor and autonomic symptoms may appear, but less frequently. To diagnose CIPN, a thorough patient's history and neurological examination are required. The current approach to CIPN management focuses on managing the symptoms of neuropathic pain and reducing or stopping the chemotherapy agent when CIPN manifests. There is no proven or advised prophylaxis therapy for CIPN. The point of this review was to talk about how some commonly used chemotherapy agents (such as platinum-based compounds, taxanes, vinca alkaloids, bortezomib, and thalidomide) cause CIPN, how to diagnose it, and the newest treatments that are available.

Abstract Chemotherapy in combination with immunotherapy has gradually shown substantial promise to increase T cell infiltration and antitumor efficacy. However, paclitaxel in combination with immune checkpoint inhibitor targeting PD-1/PD-L1 was only used to treat a small proportion of metastatic triple-negative breast cancer (TNBC), and the clinical outcomes was very limited. In addition, this regimen cannot prevent paclitaxel-induced peripheral neuropathy. Therefore, there was an urgent need for a novel target to enhance the antitumor activity of paclitaxel and alleviate chemotherapy-induced peripheral neuropathy in breast cancer. Here, we found that Dickkopf-1 (DKK1) expression was upregulated in multiply subtypes of human breast cancer specimens after paclitaxel-based chemotherapy. Mechanistic studies revealed that paclitaxel promoted DKK1 expression by inducing EGFR signaling in breast cancer cells, and the upregulation of DKK1 could hinder the therapeutic efficacy of paclitaxel by suppressing the infiltration and activity of CD8+ T cells in tumor microenvironment. Moreover, paclitaxel treatment in tumor-bearing mice also increased DKK1 expression through the activation of EGFR signaling in the primary sensory dorsal root ganglion (DRG) neurons, leading to the development of peripheral neuropathy, which is charactered by myelin damage in the sciatic nerve, neuropathic pain, and loss of cutaneous innervation in hindpaw skin. The addition of an anti-DKK1 antibody not only improved therapeutic efficacy of paclitaxel in two murine subtype models of breast cancer but also alleviated paclitaxel-induced peripheral neuropathy. Taken together, our findings providing a potential chemoimmunotherapy strategy with low neurotoxicity that can benefit multiple subtypes of breast cancer patients.

Abstract Introduction Therapeutic offloading devices, including insoles, shoes, and other orthoses, are some of the most commonly used interventions to treat or prevent diabetic foot ulceration. Custom-made offloading devices are increasingly used to offset the development of foot ulcers. However, whether these devices are more effective than prefabricated standard offloading devices is uncertain. Therefore, this systematic review collates and examines evidence on the efficacy of custom-made offloading devices in preventing foot ulcer incidence and recurrence in people diagnosed with diabetes. Methods Five scientific databases were searched, covering 2011–2023. Initial searches and screening were carried out independently by two researchers. Studies meeting the inclusion criteria were further examined through additional screenings, and critical appraisal. Data relevant to the review aims were extracted and analysed within a narrative synthesis. Results Of the 1,715 articles found in the initial searches, nine papers were found to meet inclusion criteria and were included in the review. The evidence shows that custom-made offloading devices are likely to be more effective for reducing or preventing diabetic foot ulcers than standard offloading devices. However, due to a lack of data it remains uncertain whether custom-made offloading devices are more cost-effective for preventing ulceration compared to standard insoles. Likewise, due to measurement heterogeneity between studies and lack of data, it is unclear whether adherence is higher in users of custom-made offloading devices, and whether such devices deliver significantly greater reductions in peak pressure as compared to standard offloading devices. Conclusion Custom-made offloading devices are more effective than standard devices for preventing diabetic foot ulceration, and we recommended their use when feasible; however, there remains uncertainty regarding their cost-effectiveness compared to standard insoles and offloading devices.

Introduction: Peripheral neuropathy is common in clinical practice, with a reported prevalence of 2.4% in the general population. There are numerous aetiologies for peripheral neuropathy like diabetes, ischaemia, vasculitis, inflammatory demyelinating disorders, nutritional deficiencies, paraproteinemic disorders, paraneoplastic syndromes, toxic exposures, and hereditary neuropathies. An exhaustive haematological, biochemical, and serological work-up, cerebrospinal fluid evaluation, electrodiagnostic tests, and nerve biopsy are required when overlapping clinical features present a diagnostic challenge. Aim: To analyse the histopathological characteristics of nerve biopsies in individuals with peripheral neuropathy. Materials and methods: This cross-sectional study was conducted in the Department of Pathology at Kasturba Medical College from January 2011 to December 2016. Nerve biopsies received in the Department of Pathology, Kasturba Medical College and Hospitals in the Ambedkar Circle and Attavar area, as well as at Government Wenlock Hospital, Mangaluru, Karnataka, India were studied. Clinical and laboratory data were collected from biopsy requisition forms and patient case records from the aforementioned hospitals. Results were presented in numbers and percentages. Results: A total of 134 nerve biopsies were included in the study. The age range of all cases studied was 7-86 years, with a mean age of 51.8 years. The study population consisted of 63.4% males and 36.6% females, resulting in a male-to-female ratio of 1.7:1. Vasculitic Neuropathy (VN) accounted for 38.1% cases, followed by chronic inflammatory neuropathies (21.7%) and Diabetic Neuropathy (DN) (12.6%). Other diagnosis included ischaemic neuropathy (6.7%), Hereditary Motor and Sensory Neuropathy (HMSN) (3.7%), subacute inflammatory demyelinating neuropathy (3.0%), as well as two cases each of Hansen’s neuritis, amyloid neuropathy, and acute inflammatory demyelinating neuropathy (1.5% each). One case of toxic neuropathy (0.7%) was identified, while 9.0% of cases displayed histological features that were either non specific or not characteristic of any specific diagnosis. Conclusion: Vasculitic neuropathy was found to be the most common aetiology of peripheral neuropathy, followed by Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and DN. The histopathological examination of nerve biopsies is a useful tool in distinguishing between diseases with overlapping clinical features, confirming or excluding vasculitis, and diagnosing hereditary conditions in settings where genetic testing is unavailable or unaffordable.

Andreas Clipet-Jensen, Hans Fjeldsøe-Nielsen, Peter Roy Kirkegaard Department of Anesthesiology and Intensive Care Medicine, Zealand University Hospital, Nykøbing, DenmarkCorrespondence: Andreas Clipet-Jensen, Email andreas.clipet-jensen.01@regionh.dk; a.clipet.jensen@gmail.comAbstract: Although peripheral nerve blocks are deemed very safe, a significant number of patients for whom this anesthetic technique may be particularly appealing to apply may present with preexisting peripheral neuropathies, putting them at risk for further nerve damage. We present a case with a 74-year-old male with several risk factors for peripheral neuropathy who developed a foot drop following a popliteal sciatic nerve block with ropivacaine. We suggest that the vasoconstrictive properties of ropivacaine may have contributed to a preexisting neuronal ischemia, thus further damaging an already compromised nerve.Keywords: peripheral nerve block, peripheral neuropathy, vasoconstriction, local anesthetics

Abstract Peripheral neuropathy and amputation are common complications of diabetes mellitus (DM) that significantly impact the quality of life of the affected individuals. This study aims to investigate the prevalence of peripheral neuropathy, the level of amputation, and the quality of life in patients with DM. This cross-sectional study was conducted after approval of the synopsis involving 225 diagnosed patients with DM on pre-defined eligibility criteria, selected from public sector OPDs, specialized diabetes centres, and centres manufacturing orthotics and prosthetics. Data were collected through interviews, observations, and the administration of the Michigan Neuropathy Screening Instrument and the Asian Diabetes Quality of Life Questionnaire. The level of amputation was recorded for each participant. Data was entered into SPSS, and results were synthesized. Pearson correlation is applied to find an association between gender and the quality of life of the participants, while P ≤ 0.05 will be considered significant. The prevalence of peripheral neuropathy in a sample of 225, based on a self-administered questionnaire, was (44.4%), and in terms of foot examination was (51.1%). As people progressed in age, the prevalence increased to 20.0% in patients above 60 years and 8.9% in ≤ 35 years of age. The majority of participants (56.0%) have had DM for less than five years. Females were 57.8% of the study population, while 97.8% of participants had type II DM. Below-knee amputation of the right limb was observed in 22(9.8%) of the participants. The QoL was poor in the majority of the participants (96.9%) patients with DM (P = 0.638 and T = -0.471). This cross-sectional study highlights a high prevalence of peripheral neuropathy and amputation and poor QoL in patients with diabetic mellitus.

Objectives: Diabetic foot syndrome is becoming increasingly common in India with a prevalence ranging from 24.9% to 49%. Diabetic foot syndrome patients have an increased likelihood of developing ulcers in their feet. Accordingly, this study evaluates the influence of photobiomodulation on altered plantar pressure distribution and ankle biomechanics in individuals with diabetic foot syndrome. Methods: A total of 20 diabetic foot syndrome patients with an absence of 10 g monofilament in one out of six sites at the plantar surface of feet, a biothesiometer for vibration perception threshold of >20 V, and diminished or absent ankle reflexes were included. The evaluation of ankle biomechanics was performed by SIMI motion analysis. In addition, the plantar pressure distribution was measured by the WinTrack pressure platform at baseline and the end of 10 sessions. They were treated with scanning mode on the foot plantar surface and probe laser at the popliteal fossa region for three sessions per week, for ten sessions. Results: Plantar pressure parameters were significantly improved (P

BackgroundPeripheral nerve injuries (PNIs) are associated with significant physical and psychological challenges, impacting both functional recovery and quality of life. Despite the physical focus of traditional treatments, psychological factors play a crucial role in the outcomes of PNI repair and recovery.ObjectivesThis systematic review aims to evaluate the impact of psychological and social factors on the repair and recovery of peripheral nerve injuries.MethodsA comprehensive literature search was conducted in PubMed/Medline, EMBASE, and Cochrane databases, covering studies from January 1985 to December 2022. A total of 36,190 records were identified, and after screening with Rayyan AI and applying inclusion criteria, 111 articles were selected for review.ResultsThe review highlights that pre-existing psychological conditions, as well as psychological responses to the injury and treatment, significantly influence recovery outcomes in PNI patients. Psychological interventions, when integrated into standard care, may improve functional recovery and quality of life.ConclusionsPsychosocial factors are critical in the management of PNIs and should be incorporated into treatment algorithms to enhance patient outcomes. Future research should focus on developing and integrating psychological support strategies in PNI treatment protocols.

Background: Peripheral neuropathy can affect balance and increase fall risk. Tai Chi is known to activate neuromuscular systems and may help improve balance and postural control. We conducted a scoping review of clinical studies that evaluated the impact of Tai Chi on balance and related neurobiological outcomes among individuals with peripheral neuropathy. Methods: We systematically searched three databases from inception to December 19, 2023 and identified 11 eligible clinical studies. We extracted trial information from each study and performed a qualitative study features analysis to summarize the clinical evidence and neurobiological mechanisms of Tai Chi in regulating balance among people with peripheral neuropathy. Results: We found that among 508 participants with clinical peripheral neuropathy, Tai Chi significantly improved single leg stance, 6-min walk, timed up-and-go tests, and gait speed when measured pre- and post-exercise. However, the differences between Tai Chi and sham exercise control that involved active calisthenics and stretching exercises were not statistically significant. Studies that used quantitative sensory testing showed that Tai Chi was associated with significant increases in plantar vibration and tactile sensitivity. The effect of Tai Chi on postural control varied depending on plantar sensory loss status, and results on muscle strength remained mixed. Other neurobiological effects involve strengthening muscle performance and proprioception and consolidating cognitive awareness of walking strategy and practical behavioral techniques. Conclusions: The findings indicated that Tai Chi may enhance balance, postural control, and gait speed in patients with peripheral neuropathy, possibly through sensory restoration, although further research is needed to confirm this. Whether Tai Chi improves muscle strength or other gait health parameters is inconclusive. Rigorous randomized clinical trials should be conducted to determine the effect of Tai Chi on balance in this population by measuring functional balance and quantitative sensory outcomes.

PurposeDiabetic keratopathy has gained increasing attention due to advancements in diagnostic and therapeutic techniques a. This article presents a visual and bibliometric analysis to illustrate the knowledge network, research hotspots, trends, and potential future directions in this field.MethodsWe retrieved articles published since 2000 from the Web of Science and analyzed the authors, institutions, countries, keywords, citations, and co-citations of these articles with VOSviewer and CiteSpace.ResultsA total of 706 highly relevant articles were identified, with the United States, China and England as major contributors; the University of Manchester, Queensland University of Technology and Weill Cornell Medical−Qatar as key institutions; and Malik Rayaz, Efron Nathan and Ferdousi Maryam as prominent authors. High-citation articles have focused mainly on corneal confocal microscopy and diabetic peripheral neuropathy. Keywords form two clusters: one around complications, diabetes and cornea sensitivity, and another around corneal confocal microscopy and peripheral neuropathy.ConclusionThe identification of diabetic peripheral neuropathy via corneal confocal microscopy has been a major focus of research in this field, but the mechanisms underlying diabetic corneal neuropathy still require further investigation and breakthroughs.

Background and aims: Normative values are lacking regarding intraepidermal nerve fiber density (IENFD) in thin sections of 5 µm. Thus, we aimed to assess IENFD in thin sections in a healthy adult population as well as to investigate whether IENFD is related to age, sex, and site of excision. Methods: Archival skin biopsies or excisions at the Department of Pathology, Lund, Sweden, from arm and leg were collected, re-sectioned, and immunohistochemically stained for Protein Gene Product 9.5 during 2020–2023. Nerve fibers were manually quantified in the 5 µm thin sections, and IENFD was compared between age groups, sex, and excision sites. Results: IENFDs were evaluated in 602 samples from 591 healthy adults aged 18 to 97 years (295 women, 296 men). Median IENFD values are presented, stratified by age groups, sex, and excision sites. Higher IENFD was observed in the arm compared to the leg, as well as in the proximal compared to the distal leg, however not across all age groups. Levels of IENFD were lower among older adults, compared to all younger groups. Conclusion: We have presented data on IENFD in thin 5 µm sections from a healthy adult population. Despite differences in IENFD observed across age groups, sexes, and excision sites, no strong conclusions regarding affecting factors could be drawn except that individuals > 65 years present with lower IENFD. Additional research and development of the method are warranted.

Summary: Nuclear pore complexes (NPCs) regulate nucleocytoplasmic transport and are anchored in the nuclear envelope by the transmembrane nucleoporin NDC1. NDC1 is essential for post-mitotic NPC assembly and the recruitment of ALADIN to the nuclear envelope. While no human disorder has been associated to one of the three transmembrane nucleoporins, biallelic variants in AAAS, encoding ALADIN, cause triple A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia, and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints. In this report, diagnostic exome and/or RNA sequencing was performed in seven individuals from four unrelated consanguineous families with AAAS-negative triple A syndrome. Molecular and clinical studies followed to elucidate the pathogenic mechanism. The affected individuals presented with intellectual disability, motor impairment, severe demyelinating with secondary axonal polyneuropathy, alacrima, and achalasia. None of the affected individuals has adrenal insufficiency. All individuals presented with biallelic NDC1 in-frame deletions or missense variants that affect amino acids and protein domains required for ALADIN binding. No other significant variants associated with the phenotypic features were reported. Skin fibroblasts derived from affected individuals show decreased recruitment of ALADIN to the NE and decreased post-mitotic NPC insertion, confirming pathogenicity of the variants. Taken together, our results implicate biallelic NDC1 variants in the pathogenesis of polyneuropathy and a triple A-like disorder without adrenal insufficiency, by interfering with physiological NDC1 functions, including the recruitment of ALADIN to the NPC.

Despite the extraordinary anti-tubercular activity of isoniazid (INH), the drug-induced hepatotoxicity and peripheral neuropathy pose a significant challenge to its wider clinical use. The primary cause of INH-induced hepatotoxicity is in vivo metabolism involving biotransformation on its terminal -NH2 group owing to its high nucleophilic nature. The human N-acetyltransferase-2 enzyme (NAT-2) exploits the reactivity of INH’s terminal -NH2 functional group and inactivates it by transferring the acetyl group, which subsequently converts to toxic metabolites. This -NH2 group also tends to react with vital endogenous molecules such as pyridoxine, leading to their deficiency, a major cause of peripheral neuropathy. The elevation of liver functional markers is observed in 10%–20% of subjects on INH treatment. INH-induced risk of fatal hepatitis is about 0.05%–1%. The incidence of peripheral neuropathy is 2%–6.5%. In this review, we discuss the genesis and historical development of INH, and different reported mechanisms of action of INH. This is followed by a brief review of various clinical trials in chronological order, highlighting treatment-associated adverse events and their occurrence rates, including details such as geographical location, number of subjects, dosing concentration, and regimen used in these clinical studies. Further, we elaborated on various known metabolic transformations highlighting the involvement of the terminal -NH2 group of INH and corresponding host enzymes, the structure of different metabolites/conjugates, and their association with hepatotoxicity or neuritis. Post this deliberation, we propose a hydrolysable chemical derivatives-based approach as a way forward to restrict this metabolism.

BackgroundHereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited systematic disease primarily affecting the peripheral and autonomic nervous system, heart, eyes and kidney. Over 140 variants have been identified worldwide, with the Gly103Arg variant reported exclusively in China. This variant is characterized by early onset eye manifestations, making accurate and timely diagnosis difficult. Therefore, we conducted a case study and literature review to investigate the clinical characteristics of the Gly103Arg variant in hereditary transthyretin amyloidosis.MethodsWe identified three patients and an asymptomatic carrier in a four-generation family by sequencing the TTR gene. The proband underwent a lumbar puncture, electromyography, abdominal fat biopsy, among other tests. Case reports of Gly103Arg variant were retrieved through a literature search for an analysis of clinical characteristics.ResultsThe study included clinical data of 44 patients. Our literature review collected data on 41 patients and the present report supplied 3 patients with the Gly103Arg variant. The mean age at onset was 39.1 ± 4.27 years (range 30–47 years) with a female ratio of 52.3%. All cases were reported in China, predominantly in southern regions, especially Yunan and Guizhou Provinces. The initial manifestation was blurred vision, except for one case presenting with numbness in the upper extremities. All of them had vitreous opacity; 17 cases had peripheral neuropathy,6 cases had autonomic neuropathy, and 3 cases had cardiopathy. No disease-related deaths have been reported to date.ConclusionThe Gly103Arg variant is unique to the Chinese population, frequently occurring in southern China. The main clinical manifestations are blurred vision, vitreous opacity, and neuropathy, with cardiopathy being rare. ATTRv should be considered if a patient diagnosed with CIDP does not respond to related therapy. Abdominal fat biopsy is a convenient and accurate diagnostic method.

BackgroundThe use of corticosteroids has become a part of the standard of care in various pathologies but their use in peripheral nerve injury treatment is limited. Given corticosteroids’ anti-inflammatory properties and their regulatory role in neuronal protein production and myelination, corticosteroids could serve as an adjunct therapy for peripheral nerve injuries. This review aims to systematically investigate the current use of corticosteroid treatment in peripheral nerve pathologies.MethodsThe systematic search was performed on PubMed, MEDLINE, EMBASE, Scopus, Cochrane, and Web of Science using keywords such as “corticosteroid treatment,” “peripheral nerve damage,” “peripheral neuropathy,” and “complications.” The PRISMA guidelines were used to conduct the systematic review and all articles were reviewed by the corresponding author. After the initial search, individual study titles and abstracts were further screened and categorized using an inclusion and exclusion criteria followed by a final full-text review.ResultsOut of the total 27,922 identified records, 203 studies were included based on the selection criteria. These studies focused on the use and efficacy of steroids across a spectrum of compression and non-compression peripheral neuropathies such as cubital tunnel syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Various studies noted the promising role of steroids in offering pain relief, nerve block, and nerve regeneration effects. Additionally, safety considerations and potential complications regarding steroid use in peripheral nerve injuries were analyzed.ConclusionWhile there is currently limited clinical utilization of corticosteroids in peripheral nerve pathologies, the anti-inflammatory and regenerative effects that steroids provide may be a beneficial tool in managing various peripheral neuropathies and their associated pain. Additional clinical trials and investigation into the mechanism of action could improve the reputation of steroid use as peripheral nerve injury treatment.

BackgroundMicroRNAs (miRNAs) in Schwann cells (SCs) mediate peripheral nerve function. Ablating Dicer, a key gene in miRNA biogenesis, in SCs causes peripheral neuropathy. Exosomes from healthy SCs (SC-Exo) ameliorate diabetic peripheral neuropathy in part via miRNAs. Thus, using transgenic mice with conditional and inducible ablation of Dicer in proteolipid protein (PLP) expressing SCs (PLP-cKO), we examined whether SC-Exo could reduce peripheral neuropathy in PLP-cKO mice.MethodsPLP-cKO mice at the age of 16 weeks (8 week post-Tamoxifen) were randomly treated with SC-Exo or saline weekly for 8 weeks. Age-and sex-matched wild-type (WT) littermates were used as controls. Peripheral neurological functions, sciatic nerve integrity, and myelination were analyzed. Quantitative RT-PCR and Western blot analyses were performed to examine miRNA and protein expression in sciatic nerve tissues, respectively.ResultsCompared to the WT mice, PLP-cKO mice exhibited a significant decrease in motor and sensory conduction velocities, thermal sensitivity, and motor coordination. PLP-cKO mice exhibited substantial demyelination and axonal damage of the sciatic nerve. Treatment of PLP-cKO mice with SC-Exo significantly ameliorated the peripheral neuropathy and sciatic nerve damage. PLP-cKO mice showed a substantial reduction in a set of Dicer-related miRNAs known to regulate myelination, axonal integrity, and inflammation such as miR-138, −146a and − 338 in the sciatic nerve. In addition, PLP-cKO mice exhibited significant reduction of myelin forming proteins, early growth response 2 (EGR2) and sex determining region Y-box10 (Sox10), but significantly increased myelination inhibitors, Notch1, c-Jun, and Sox2 and the axonal growth inhibitor phosphatase and tens in homolog (PTEN). However, SC-Exo treatment reversed the PLP-cKO altered miRNAs and proteins.ConclusionThis study demonstrates that exogenous SC-Exo ameliorate peripheral neuropathy induced by Dicer ablation in PLP expressing SCs. The therapeutic benefit may be mediated by the SC-Exo altered miRNAs and their targeted genes.

Abstract Background A growing body of research indicates that poor functional status before chemotherapy may be correlated with the severity of chemotherapy-induced peripheral neuropathy (CIPN) after the neurotoxic treatment. However, little is known about the associations between pre-chemotherapy physical function and CIPN in patients with pancreatic cancer. Purpose To identify the predictors of CIPN in relation to pre-chemotherapy physical function in patients with pancreatic cancer. Methods This secondary analysis included data from patients with pancreatic cancer who participated in a longitudinal research study at National Cheng Kung University Hospital, Tainan, Taiwan. Four physical function tests (i.e., grip strength, Timed Up and Go (TUG), 2-minute step test (2MST), and Romberg test) and two questionnaires (The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30] and Chemotherapy-Induced Peripheral Neuropathy Module [CIPN20]) were assessed at baseline (i.e., before first chemotherapy session) and 2-, 3-, 4-, and 6-month follow-up. Multiple linear regression with adjustment for confounding factors was used to assess the associations between the four functional tests at baseline and the CIPN20 total score and individual subscale scores (sensory, motor, and autonomic) at 6-month follow-up. Results Data from a total of 209 pancreatic cancer patients (mean age: 64.4 years, 54.5% male) were analyzed. The findings showed that the severity of CIPN at 6-month follow-up was significantly associated with the baseline TUG completion time (β = 0.684, p = 0.003). The TUG completion time was also positively correlated with the 6-month CIPN sensory and autonomic subscales. In addition, a baseline positive Romberg test (β = 0.525, p = 0.009) was a significant predictor of the severity of motor neuropathy at 6-month follow-up. Conclusion The TUG completion time and positive Romberg test before chemotherapy may be predictive factors of the CIPN severity 6 months after the commencement of chemotherapy. Accordingly, the incorporation of TUG and Romberg tests into the clinical assessment protocol emerges as imperative for individuals diagnosed with pancreatic carcinoma undergoing chemotherapy regimens.

Natalie R Barnett,1 Amanda M Bunnell,1 Matthew A Dow2 1Department of Anesthesiology and Perioperative Medicine, Medical University of South Carolina, Charleston, SC, USA; 2Department of Orthopaedics and Physical Medicine, Medical University of South Carolina, Charleston, SC, USACorrespondence: Natalie R Barnett, Associate Professor in Anesthesiology, Department of Anesthesiology and Perioperative Medicine, Medical University of South Carolina, 10 McClennan Banks Dr, Suite 2190, MSC 940, Charleston, SC, 29425, USA, Tel +1-843-792-5454, Email barnettn@musc.eduAbstract: Charcot Marie Tooth disease is a common cause of pediatric peripheral neuropathy, which can lead to distal muscle wasting and weakness necessitating orthopedic procedures. We present an eleven-year-old male with Charcot Marie Tooth disease who received peripheral nerve blocks for ankle surgery, with a total dose of 1.75 mg/kg of bupivacaine 0.25%. Upon follow-up, it was identified that the sensory blockade did not resolve until thirty-six hours, postoperatively. There were no noted long-term sequalae on surgical follow-up. If a patient with Charcot Marie Tooth receives a peripheral nerve block, the patient should receive close short- and long-term follow-up to monitor for block complication or disease exacerbation.Keywords: regional anesthesia, local anesthesia, peripheral neuropathy

Abstract Background Peripheral neuropathy (PN) is increasingly recognized in Parkinson’s disease (PD). This study aimed to evaluate peripheral nerve and autonomic nervous system dysfunction in PD. Forty patients with PD (20 drug-naïve, 20 on treatment) and 20 controls underwent neurological examination, Toronto Clinical Neuropathy Score (TCNS), nerve conduction studies, autonomic function tests including (heart rate variability, Blood pressure changes with standing and sustained handgrip, and sudomotor pathways. The Ewing classification system scored each test to quantify autonomic failure severity). Laboratory tests (B12, homocysteine, methylmalonic acid). Results Treated patients with PD had higher MDS-UPDRS scores than drug-naïve (p = 0.001). TCNS indicated mild PN in some drug-naïve patients, and mild–moderate PN in treated patients. Nerve conduction studies showed significant sensory and motor neuropathy in treated versus drug-naïve PD and controls. Treated patients had lower B12, higher homocysteine/methylmalonic acid than other groups. Across autonomic tests, controls had the most normal results, followed by drug-naïve patients, with treated patients being most abnormal. Autonomic dysfunction correlated with disease duration, severity, L-dopa dose. Lower B12, higher homocysteine/methylmalonic acid levels were associated with greater neuropathy and disease severity. Conclusion Patients with PD show evidence of PN and autonomic dysfunction, which is milder in drug-naïve patients but worsens with disease progression and treatment. Peripheral nervous system assessments may help diagnose and monitor PD neuropathy and effects of interventions.

Runbing Xu,1,&ast; Changhe Yu,2,&ast; Xinyu Zhang,1 Yipin Zhang,1 Mengfei Li,1 Bei Jia,1 Shiyan Yan,3 Miao Jiang1,4 1Hematology and Oncology Department, Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, Beijing, People’s Republic of China; 2Tuina and Pain Management Department, Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, Beijing, People’s Republic of China; 3School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 4School of Life Science, Beijing University of Chinese Medicine, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Miao Jiang, School of Life Science, Beijing University of Chinese Medicine, Gongchen Street, Beijing, People’s Republic of China, Tel +8613511072205, Email doctorjiang@139.com Shiyan Yan, School of Acupuncture-Moxibustion and Tuina, Gongchen Street, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, Tel +8613521436209, Email yanshiyan0927@sina.comPurpose: To determine the efficacy and safety of a neuromodulation intervention regimen in the treatment of chemotherapy-induced peripheral neuropathy (CIPN).Patients and Methods: Systematic searches were conducted in seven English databases. Randomized controlled trials of all neuromodulation interventions (both invasive and non-invasive) for the treatment of CIPN were selected. Group comparisons of differences between interventions and controls were also made. We divided the outcomes into immediate-term effect (≤ 3 weeks), short-term effect (3 weeks to ≤ 3 months), and long-term effect (> 3 months).Results: Sixteen studies and 946 patients with CIPN were included. Among immediate-term effects, neuromodulation interventions were superior to usual care for improving pain (SMD=− 0.77, 95% CI − 1.07~ 0.47), FACT-Ntx (MD = 5.35, 95% CI 2.84~ 7.87), and QOL (SMD = 0.44, 95% CI 0.09~ 0.79) (moderate certainty); neuromodulation loaded with usual care was superior to usual care for improving pain (SMD=− 0.47, 95% CI − 0.71 ~ − 0.23), and QOL (SMD = 0.40, 95% CI 0.12 ~ 0.69) (moderate certainty). There were no statistically significant differences between the neuromodulation interventions regimen vs usual care in short- and long-term outcomes and neuromodulation vs sham stimulation from any outcome measure. There were mild adverse events such as pain at the site of stimulation and bruising, and no serious adverse events were reported.Conclusion: Neuromodulation interventions had significant immediate-term efficacy in CIPN but had not been shown to be superior to sham stimulation; short-term and long-term efficacy could not be determined because there were too few original RCTs. Moreover, there are no serious adverse effects of this therapy.Keywords: chemotherapy, peripheral neuropathy, neuromodulation, systematic review, meta-analysis

Abstract 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 Background Diabetic foot disease (DF) is a common diabetes-related complication; however, the prevalence and associated risk factors for DF are not well characterised among people living with diabetes (PLWD) in Zimbabwe. This may suggest the unavailability of adequate strategies to diagnose and treat DF in the country. This study aimed to determine the prevalence of DF and associated risk factors for PLWD in Harare, Zimbabwe. Methods This was a cross-sectional study, employing a quantitative approach. In total, 352 PLWD were recruited from 16 primary care clinics in Harare. Sociodemographic and clinical data were collected via face-to-face interviews and clinical records reviews. The DF screening included an evaluation for peripheral neuropathy, ankle-brachial index (ABI), ulceration, and amputation. Self-administered questionnaires were used to assess knowledge, attitudes, and practices (KAPs), and KAP was scored using Bloom’s cut-off. Chi-Square goodness-of-fit tests were performed, and regression analyses were used for association analysis. The threshold for significance was p 0.05). Conclusion This study showed that there was a high prevalence of DF (53%) in PLWD in Zimbabwe, and insulin use was protective against DF. There is an urgent need for policy revisions to include foot screening in routine primary care and increasing insulin use for PLWD to prevent complications such as DF as an integral part of primary care.

Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes, which can lead to neuropathic pain, foot ulcers, and even disability, and greatly reduces survival. Therefore, early diagnosis and prevention of DPN is of great importance to reduce symptoms and disability rate. Ultrasound elastography is a noninvasive method to evaluate changes in nerve tissue composition by obtaining the elastic modulus of tissue and visually displaying the stiffness in the form of images. This paper summarizes the application progress of ultrasound elastography in the evaluation of peripheral neuropathy in recent years, in order to provide reference for the future clinical application of large samples.

BackgroundMinichromosome maintenance complex component 3 associated protein (MCM3AP) is a gene in which mutations can result in autosomal recessive peripheral neuropathy with or without impaired intellectual development. The MCM3AP genotype-phenotype correlation and prognosis remain unclear. The aim of this study was to explore the genotype–phenotype correlations pertaining to MCM3AP.MethodsWhole-exome sequencing (WES) combined with copy number variation sequencing (CNV-seq) were performed on the genomic DNA isolated from a Chinese family, and Sanger sequencing, quantitative PCR and cDNA analyses were performed to examine the mutations. The retrospective study was conducted on 28 individuals with biallelic MCM3AP mutation-related diseases, including features such as mutations, motor development impairment, intellectual disability, weakness/atrophy, and cerebral magnetic resonance imaging abnormalities.ResultsSequencing identified novel compound heterozygous mutations in MCM3AP, namely, a paternal variant c.1_5426del (loss of exons 1–25) and a maternal splicing variant c.1858 + 3A>G. Functional studies revealed that the variant c.1858 + 3A>G resulted in the heterozygous deletion of exon 5, thereby affecting splicing functionality. Furthermore, the compound heterozygous mutation may affect the functionality of the protein domain. Retrospective analysis revealed different genotype–phenotype correlations for the pathogenic variants in biallelic MCM3AP: all individuals (100%) with mutations outside the Sac3 domain exhibited early-onset symptoms, motor developmental delays, and cognitive abnormalities, conversely, the proportions of individuals carrying mutations within the domain were 26.7% (motor delays) and 46.7% (cognitive abnormalities).ConclusionOur findings further expand the genetic mutation spectrum of biallelic MCM3AP and highlight the genotype-phenotype associations. Additionally, we elaborate on the importance of rehabilitation intervention.

BackgroundPeripheral neuropathy (PN) is a common neurological disorder, and circulating plasma proteins with causal genetic evidence are a major source of therapeutic targets. This study identifies several potential plasma proteins that are causally related to PN risk, providing new insights into protein-mediated pathogenesis of PN and potential targets for novel therapies.MethodsTo identify potential therapeutic targets for PN, we employed two-sample Mendelian randomization (MR) to identify plasma proteins associated with six common PN. First, we screened for proteins related to PN using genome-wide association studies (GWAS), obtaining genetic data on plasma proteomes from 35,559 Icelanders. Summary data for six common PN, including Carpal Tunnel Syndrome (CTS), Trigeminal Neuralgia (TN), Alcoholic Neuropathy (AIP), Drug-induced Neuropathy (DIP), Diabetic Neuropathy (DP), and Guillain-Barré syndrome (GBS), were obtained from the FinnGen database. Two-sample MR and colocalization analyses were then conducted to further identify protein-PN pairs with presumed causal relationships. Enrichment analysis of positive proteins revealed potential biological processes and pathways. Based on drug-gene interaction analysis, we ultimately identified causal proteins associated with PN that could serve as potential drug targets for treating PN.ResultsThrough MR analysis, we identified eight proteins (UBC12, SEM4C, IL23R, Prothrombin, CBS, Microglobulin, MATN4, COLEC12) with causal relationships to PN. We found that UBC12 is a protective factor for DP and CTS, while the remaining proteins are risk factors. Further colocalization analysis showed a posterior probability of hypothesis 4 (PPH4) less than 0.75, indicating no positive colocalization results were found. From the pathway enrichment analysis, we discovered that the proteins were mainly concentrated in pathways related to defense response to bacterium, receptor signaling pathway via STAT, cell killing, negative regulation of cytokine production, and leukocyte mediated immunity. Finally, in Drug-Gene Interaction database (DGIdb), we identified three protein-coding genes (IL23R, F2, CBS) as potential drug targets for PN.ConclusionMendelian randomization studies confirm the causal relationship between genetically predicted PN-related risk and genetically predicted plasma protein abundance. Plasma proteins, as biomarkers associated with PN, can provide potential drug targets for etiological intervention research in PN.

Abstract Background Survivors of childhood central nervous system (CNS) tumors can develop motor and sensory impairment from their cancer and treatment history. We estimated the prevalence of motor and sensory impairment in survivors compared with controls through clinical assessment and identified associated treatment exposures and functional, quality of life (QOL), and social outcomes. Methods Survivors of childhood CNS tumors from the St. Jude Lifetime Cohort (n = 378, median [range] age 24.0 [18.0–53.0] years, 43.4% female) ≥5 years from diagnosis and controls (n = 445, median [range] age 34.0 [18.0–70.0] years, 55.7% female) completed in‐person evaluation for motor and sensory impairment using the modified Total Neuropathy Score. Impairment was graded by modified Common Terminology Criteria for Adverse Events. Multivariable models estimated associations between grade ≥2 motor/sensory impairment, individual/treatment characteristics, and secondary outcomes (function by Physical Performance Test, fitness by physiologic cost index, QOL by Medical Outcomes Survey Short Form‐36 physical/mental summary scores, social attainment). Results Grade ≥2 motor or sensory impairment was more prevalent in survivors (24.1%, 95% Confidence Interval [CI] 19.8%–29.4%) than controls (2.9%, CI 1.4–4.5%). Among survivors, in multivariable models, motor impairment was associated with vinca exposure 2036 mg/m2 versus none (OR 12.61, CI 2.19–72.72). Sensory impairment was associated with older age at diagnosis (OR 1.09, CI 1.01–1.16) and craniospinal irradiation versus none (OR 4.39, CI 1.68–11.50). There were lower odds of motor/sensory impairment in survivors treated in the year 2000 or later versus before 1990 (Motor: OR 0.29, CI 0.10–0.84, Sensory: OR 0.35, CI 0.13–0.96). Motor impairment was associated with impaired physical QOL (OR 2.64, CI 1.22–5.72). Conclusions In survivors of childhood CNS tumors, motor and sensory impairment is prevalent by clinical assessment, especially after exposure to etoposide, vinca, or craniospinal radiation. Treating motor impairment may improve survivors' QOL.

Background: There remains a paucity of research comparing the diagnostic and therapeutic outcomes between Magnetic Resonance Imaging (MRI) and x-ray modalities for Charcot neuro-osteoarthropathy CNO. This retrospective study investigates the use of offloading devices, duration of offloading and final footwear outcomes dependent on imaging at diagnosis. Methods: Medical records from a secondary hospital high-risk foot clinic in Perth, Western Australia, were systematically reviewed. Data collected included baseline medical history, location of CNO, Eichenholtz stage or Chantelau and Grutznel grade at diagnosis, type and duration of offloading, and final footwear outcomes. Results: Twenty-eight patients met the inclusion criteria. All had diabetes and peripheral neuropathy. All patients received either an MRI (43%) or x-ray (57%) to confirm the diagnosis of active CNO. Five (17.9%) patients who were diagnosed on MRI had grade 0 CNO whilst 23 (82.1%) patients who were diagnosed on x-ray had stage 1 CNO. No statistical significance was found between the type and duration of offloading, resolution of CNO, footwear and transtibial amputation (TTA) outcomes across those diagnosed with MRI or x-ray. Conclusion: No statistical significance in patient outcomes was found between those diagnosed with grade 0 on MRI and those diagnosed with stage 1 on x-ray.

BackgroundThe treatment of multidrug-resistant tuberculosis (MDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) remains challenging due to the limited availability of effective drugs. Linezolid has emerged as a promising therapeutic option for these cases. However, its long-term use can lead to complications such as peripheral and optic neuropathies. Acupuncture, a cornerstone of traditional Chinese medicine, has been shown to be effective in the treatment of peripheral neuropathy (PN). This study examines the potential benefits of acupuncture in the treatment of linezolid-induced peripheral neuropathy (LIPN).MethodsFour patients, aged 27 to 60 years, diagnosed with LIPN, underwent daily acupuncture treatments. The main endpoint was to assess the efficacy of acupuncture in reducing neuropathic pain associated with LIPN in patients. This was primarily measured using changes in the Short Form McGill Pain Questionnaire (SF-MPQ) scores before and after acupuncture treatment.ResultsThree of the patients experienced significant symptom remission, while one experienced marginal improvement. Treatments ranged from 7 to 18 sessions. Specifically, the first patient reported substantial relief with a score reduction from 33 to 13; the second patient observed minimal change; the third patient’s score decreased dramatically from 10 to 2 after eight sessions; the last patient had a score reduction from 21 to 12 after five sessions, but did not continue treatment for a second assessment.ConclusionAcupuncture is a promising therapeutic approach for LIPN. However, larger and more thorough studies are needed to determine its full potential.

A 19-year-old man presented with recurrent intermittent fever, progressive limbs weakness, numbness, and atrophy for 5 years. Biopsy of the sural nerve, spleen, lymph nodes, bone marrow and labial gland revealed that monomorphic small lymphoid cells infiltrated diffusely and that there was severe loss of large myelinated nerve fibers. Immunohistochemically, these cells were mainly CD8-positive T cells and were positive for CD3 and CD57. This patient was diagnosed as indolent CD8-positive T lymphoproliferative disorder (indolent CD8-positive T-LPD), emphasizing the need for a broad differential diagnosis under these conditions, and nerve biopsy should be performed.

Aysha A AlShareef,1,2,&ast; Moafaq S Alrawaili,1,2,&ast; Salwa Awwadh Almutairi,3 Mustafa Mohammad Ayyad,3 Weam Alshora4 1Department of Neurology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 2Neuromuscular Medicine Unit, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia; 3Department of Neurology, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia; 4Department of Family Medicine, Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia&ast;These authors contributed equally to this workCorrespondence: Moafaq S Alrawaili, Department of Neurology, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia, Tel +966547900080, Fax +966126128188, Email alruily@kau.edu.saBackground: Diabetic neuropathy (DN) is a common complication of type 2 diabetes (T2DM) and is characterized by persistent inflammation. Hematological parameters have emerged as a novel marker for detecting chronic inflammatory conditions, including diabetes.Aim: We aim to examine the association between HbA1c levels, which can indicate the presence of diabetic neuropathy, and hematological parameters to explore the possibility of using hematological parameters as a new indicator for DN in T2DM patients.Methods: This was a retrospective study of 768 (483 males and 284 females) medical records of adult T2DM patients with or without neuropathy who attending the outpatient neuromuscular clinic at King Abdul-Aziz University Hospital from January 2016 to December 2021.Results: The results showed significant increases in HbA1c levels (p=0.000), lymphocyte levels (p=0.028), and the neutrophil-lymphocyte ratio (NLR) (p=0.011). In the T2DM group, HBA1C levels were found to be positively correlated with age (r=0.306, p=0.000), neutrophil (NEUT) (r=0. 287, p=0.000), platelet (PLT) (r=0. 148, p=0.039), and neutrophil-lymphocyte ratio (NLR) (r=0.306193, p=0.0007), and negatively correlated with gender (r=− 0.306193, p=0.0007). In the T2DMN group, HBA1C levels showed a positive correlation with hemoglobin (HB) (r=0.084, p=0.045), PLT (r=0.087, p=0.037), and PLT/mean corpuscular hemoglobin (MCH) ratio (PLT/MCH ratio) (r=0.12, p=0.004), and a negative correlation with age (r=− 0.204, p=0.000), gender (r=− 0.086, p=0.041), weight (WT) (r=− 0.113, p=0.007), Body Surface Area (BSA) (r=− 0.09, p=0.031), mean corpuscular volume (MCV) (r=− 0.292, p=0.000), and MCH (r=− 0.186, p=0.000).Conclusion: Our study found a significant association between HbA1c, a biomarker for diabetic neuropathy, and various hematological parameters (HB, MCV, MCH, PLT, PLT/MCH ratio) in T2DMN patients. By effectively controlling and monitoring these variables, it may be feasible to prevent or delay the progression of peripheral neuropathy in diabetic patients. However, further research is needed to validate these findings.Plain Language Summary: DN is nerve damage induced by elevated blood glucose levels in T2DM. It is a common condition that affects patients by increasing the chance of falling, causing discomfort, and decreasing their quality of life. It is one of the most ubiquitous consequences of diabetes. Symptoms include limb numbness, tingling, weakness, and severe pain and sensitivity. Long-term microvascular effects of diabetes mellitus include retinopathy, nephropathy, and neuropathy. This study was done to evaluate the effects of DN on hematological parameters. The haematological parameters study aims to identify a relationship between HbA1c and DN. The researchers determined clinical data through clinical records including age, gender, WT, BSA, and laboratory data included HbA1c, HB, MCHC, MCV, MCH, PLT, RDW, HCT, NEUT, LYMPH, NLR, PLR, and PLT/MCH ratio. Statistical analysis was applied after data collection. As a result, this retrospective study identified both positive and negative correlations between HbA1c, a biomarker for diabetic neuropathy, and haematological variables in diabetic patients with neuropathy, including HB, MCV, MCH, PLT, and the PLT/MCH ratio. This finding may be used as a prognostic indicator of DN. It is crucial to manage and monitor blood sugar levels for effective treatment of this dangerous condition. Doctors advise regular walking and mild exercise to reduce neuropathy discomfort, build muscle, and regulate blood sugar levels. An in-depth investigation is required to validate the function of these parameters.Keywords: diabetic neuropathy, HbA1C, hematological profile, peripheral neuropathy, microvascular complications

Improving tactile sensation by vibrating insoles was recommended to prevent foot ulcers in diabetic peripheral neuropathy (DPN). Lack of an insole design for diabetics was a challenge. Clinical trials on applying vibrating insoles with noise and stochastic resonance (SR) stimulating tactile were also required. In this study, vibrating foot orthoses (VFO) with a total contact design based on orthotics were proposed to provide proper insoles for diabetes. This study aimed to determine if VFO were beneficial at enhancing tactile in DPN. VFO were developed in combination with individual’s custom-made foot orthoses and stimulation signals—integrating random 0–100 Hz square wave pulse signals with pseudorandom white noise by a SR approach. Sixty patients with mild-to-severe DPN were randomized to conduct crossover experiments: using and without VFO for 60 minutes stimulation at 90% of individuals’ vibration perception threshold (VPT) level. VPT values when using VFO at the 1st and 5th metatarsophalangeal joints of the left foot decreased by 9.35% ( ${P} \lt $ .001); 9.04% ( ${P} \lt $ .001), and of the right foot decreased by 7.63% ( ${P} \lt $ .001); 7.24% ( ${P}~\lt $ .001), respectively. Without VFO, there was no significant difference. Subgroups of mild and moderate DPN tended to benefit greatly from utilizing VFO. VFO can improve tactile in DPN. VFO may contribute to restoring/prolonging tactile and protective sensations, also decreasing peripheral nervous system deterioration. VFO might be useful for neurorehabilitation, and help prevent foot ulcers and disabilities.

The early diagnosis of diabetic neuropathy (DN) is fundamental in order to enact timely therapeutic strategies for limiting disease progression. In this work, we explored the suitability of standing balance task for identifying the presence of DN. Further, we proposed two diagnosis pathways in order to succeed in distinguishing between different stages of the disease. We considered a cohort of non-neuropathic (NN), asymptomatic neuropathic (AN), and symptomatic neuropathic (SN) diabetic patients. From the center of pressure (COP), a series of features belonging to different description domains were extracted. In order to exploit the whole information retrievable from COP, a majority voting ensemble was applied to the output of classifiers trained separately on different COP components. The ensemble of kNN classifiers provided over 86% accuracy for the first diagnosis pathway, made by a 3-class classification task for distinguishing between NN, AN, and SN patients. The second pathway offered higher performances, with over 97% accuracy in identifying patients with symptomatic and asymptomatic neuropathy. Notably, in the last case, no asymptomatic patient went undetected. This work showed that properly leveraging all the information that can be mined from COP trajectory recorded during standing balance is effective for achieving reliable DN identification. This work is a step toward a clinical tool for neuropathy diagnosis, also in the early stages of the disease.

Adverse drug reactions have a direct impact on the treatment effect and quality of life of patients with malignant tumors. Research has found that moxibustion can effectively relieve the chemotherapy-induced adverse drug reactions. This article summarized the interventional mechanism of moxibustion and its clinical application for relieving chemotherapy-induced adverse drug reactions, in order to guide the clinical practice and improve the quality of life of cancer patients with chemotherapy. (肿瘤化疗相关不良反应严重影响患者的治疗和生活质量。艾灸可以缓解恶性肿瘤化疗相关不良反应, 减轻患者临床症状。本研究就艾灸疗法干预机制及其用于缓解肿瘤患者化疗相关不良反应的研究现状进行综述, 以期更好地指导临床实践, 提高化疗患者的生活质量。)

Abstract Background Neuromuscular diseases (NMD) emerged as one of the main side effects of the COVID-19 vaccination. We pooled and summarized the evidence on the clinical features and outcomes of NMD associated with COVID-19 vaccination. Methods We comprehensively searched three databases, Medline, Embase, and Scopus, using the key terms covering “Neuromuscular disease” AND “COVID-19 vaccine”, and pooled the individual patient data extracted from the included studies. Results A total of 258 NMD cases following COVID-19 have been reported globally, of which 171 cases were Guillain-Barré syndrome (GBS), 40 Parsonage-Turner syndrome (PTS), 22 Myasthenia Gravis (MG), 19 facial nerve palsy (FNP), 5 single fiber neuropathy, and 1 Tolosa-Hunt syndrome. All (100%) SFN patients and 58% of FNP patients were female; in the remaining NMDs, patients were predominantly male, including MG (82%), GBS (63%), and PTS (62.5%). The median time from vaccine to symptom was less than 2 weeks in all groups. Symptoms mainly appeared following the first dose of vector vaccine, but there was no specific pattern for mRNA-based. Conclusion COVID-19 vaccines might induce some NMDs, mainly in adults. The age distribution and gender characteristics of affected patients may differ based on the NMD type. About two-thirds of the cases probably occur less than 2 weeks after vaccination.

Introduction F wave response, a late response obtained from a motor nerve, can be influenced by various external factors like gender, temperature, height, weight, and limb length, and hence it causes variation in the measured parameters. Since very few studies have studied the impact of arm length on the F wave, this study was conducted to analyze the relation between the arm length on various parameters of F wave and hence to consider the importance of it during conduct of a nerve conduction study.

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.

Aim. Evaluating pain sensation after C nociceptor activation with transdermal sinusoidal current wave stimulation protocol and skin biopsy.Materials and methods. Healthy volunteers aged 20–30 years (17 females and 18 males) participated after having given their informed consent. Half‑sine wave pulses of 0.5 sec duration (1 Hz) were generated at intensities of 0.2 to 1 mA by a constant current stimulator. Apart from half‑sine wave stimulation, sine wave pulses of 60 sec duration (4 Hz) were generated at intensity of 0.2 mA also by the constant current stimulator (Digitimer Ltd, Welwyn Garden City, UK) controlled by DAPSYS 8 (www.dapsys.net). Moreover, we performed 3‑mm skin punch biopsies 10 cm above the lateral malleolus of the leg and in the middle of the volar side of the forearm to the volunteer’s group.Results. Delivering transdermal sinusoidal half‑sine wave when trying to stimulate mechano‑sensitive C fibers, when the amplitude of the delivered wave is increased from 0.2 to 1 mA according to our protocol, pain sensation is also increased following the same scheme. If we observe a different scheme of activation in C fibers, this could be a sign of neuropathic pain. Considering the mechano‑insensitive C fibers of pain, when trying to stimulate them we expect increasing pain sensation and then familiarization, desensitization and reduction of pain sensation. As a result, if this scheme isn’t observed when sine wave is delivered transdermal with 1 min of duration, and we observe a different scheme, a C fiber neuropathy and neuropathic pain could be involved. Regarding the skin biopsies, a correlation between pain sensation of sine wave (delivered transdermal to stimulate mechano‑insensitive C fibers of pain on the forearm), and the nerve fiber density was observed. A correlation between the bifurcated fibers of the biopsy site and the pain sensation was observed when mechanosensitive and mechano‑insensitive fibers are stimulated, which needs further investigation. Also, a correlation between the remnant nerve fibers of subepidermal nerve plexus and mechano‑insensitive nerve fibers of pain is observed that also needs further investigation.Conclusion. Skin biopsy and transdermal electrical stimulation are very promising available tools of diagnosing C fiber neuropathies and assessing neuropathic pain.