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PurposeStudies on the association between peripheral neuropathy (PN) and patient-reported outcomes have mostly overlooked sleep quality. Therefore, we aimed to assess the association between PN and sleep quality in a population-based sample of colorectal cancer (CRC) patients up two years after diagnosis. MethodsAll newly diagnosed CRC patients from four Dutch hospitals were eligible for participation. Patients (N=340) completed questionnaires about PN (EORTC QLQ-CIPN20) and sleep (PSQI) before initial treatment (baseline) and one and two years after diagnosis. ResultsPatients who developed sensory PN (n=76) or motor PN (n=79) after treatment more often reported poor sleeping scores (PSQI>5) compared with those who did not develop SPN or MPN at 1-year (SPN: 38% vs. 261%, MPN: 37% vs. 14%) and 2-year follow-up (SPN: 38 vs. 23%, MPN: 37% vs. 18%) (all pConclusionsBoth SPN and MPN were significantly associated with the course of sleep quality among CRC patients up to two years after diagnosis. Clinicians should be encouraged to discuss sleep quality with their patients who either report PN or are at risk of developing PN. Implications for survivors: Improving sleep quality among survivors with PN is important, either by reducing PN symptoms, or directly targeting sleep

Diabetic mellitus is a worldwide endocrine and metabolic disorder with insulin insensitivity or deficiency or both whose prevalence could rise up to 592 million by 2035. Consistent hyperglycemia leads to one of the most common comorbidities like Diabetic Peripheral Neuropathy (DPN). DPN is underlined with unpleasant sensory experience, such as tingling and burning sensation, hyperalgesia, numbness, etc. Globally, 50-60% of the diabetic population is suffering from such symptoms as microvascular complications. Consistent hyperglycemia during DM causes activation/inhibition of various pathways playing important role in the homeostasis of neurons and other cells. Disruption of these pathways results into apoptosis and mitochondrial dysfunctions, causing neuropathy. Among these, pathways like Polyol and PARP are some of the most intensively studied ones whereas those like Wnt pathway, Mitogen activated protein kinase (MAPK), mTOR pathway are comparatively newly discovered. Understanding of these pathways and their role in pathophysiology of DN underlines a few molecules of immense therapeutic value. The inhibitors or activators of these molecules can be of therapeutic importance in the management of DPN. This review, hence, focuses on these underlying molecular mechanisms intending to provide therapeutically effective molecular targets for the treatment of DPN.

Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves1,2. Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia3–7, aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes8–10. Serine and glycine are closely related NEAAs whose levels are consistently reduced in patients with metabolic syndrome10–14, but the mechanistic drivers and downstream consequences of this metabotype remain unclear. Low systemic serine and glycine are also emerging as a hallmark of macular and peripheral nerve disorders, correlating with impaired visual acuity and peripheral neuropathy15,16. Here we demonstrate that aberrant serine homeostasis drives serine and glycine deficiencies in diabetic mice, which can be diagnosed with a serine tolerance test that quantifies serine uptake and disposal. Mimicking these metabolic alterations in young mice by dietary serine or glycine restriction together with high fat intake markedly accelerates the onset of small fibre neuropathy while reducing adiposity. Normalization of serine by dietary supplementation and mitigation of dyslipidaemia with myriocin both alleviate neuropathy in diabetic mice, linking serine-associated peripheral neuropathy to sphingolipid metabolism. These findings identify systemic serine deficiency and dyslipidaemia as novel risk factors for peripheral neuropathy that may be exploited therapeutically.

SIGNIFICANCE Reactive oxygen species (ROS) contribute to multiple aspects of peripheral nervous system (PNS) biology ranging from physiological processes (e.g. axonal outgrowth and regeneration), to pathophysiology (e.g. nerve degeneration). Although ROS are derived from multiple sources, NADPH oxidase (Nox) family members are dedicated to ROS generation. Noxs are expressed in the PNS and their overexpression is associated with detrimental effects on nerve function and contribute, at least in part, to peripheral neuropathies. Recent Advances: Of the 7 members, studies mostly focused on Nox1, Nox2, and Nox4, which are expressed in the PNS in a cell-specific manner. We have also recently identified human Nox5 in sural nerve biopsies. When maintained at homeostatic levels, Noxs regulate several aspects of peripheral nerve health, most notably neurite outgrowth and axonal regeneration following nerve lesion. While Nox2 and Nox4 dysregulation is a major source of oxidative stress in PNS disorders, including neuropathic pain and diabetic peripheral neuropathy, recent evidence also implicates Nox1 and Nox5. CRITICAL ISSUES Although there is compelling evidence for a direct role of Noxs on nerve function, little is known about their subcellular localization, intercellular regulation, and interaction. These, together with redox signaling, are considered crucial components of nerve redox status. Additionally, the lack of isoform-specific inhibitors limits conclusions about the physiological role of Noxs in the PNS and their therapeutic potential in peripheral neuropathies. FUTURE DIRECTIONS Future research using isoform-specific genetic and pharmacological approaches are therefore needed to better understand the significance of Nox enzymes in PNS (patho) physiology.

Background Most surgeons are unaware that idiopathic neuropathy, which occurs independently of mechanical injury, can present as postoperative peripheral neuropathy. The aim of this study was to reveal the presence of postoperative neuropathy considered to be induced by surgical stress and to make surgeons aware that idiopathic neuropathy can occur postoperatively. Methods We conducted a survey among orthopedic surgeons regarding patients with postoperative neuropathies of unknown cause. For each case, the type of neuropathy, preceding surgery and anesthesia, patient background, clinical findings, and clinical course were investigated. Results Seven patients were identified. The mean time from surgery to the onset of neuropathy was 9.3 days (range 1–15 days). Five of the patients fully recovered spontaneously within 1 year, while the remaining two underwent neurolysis. One patient presented with hourglass-like constrictions in the radial nerve. No inflammatory cells were found in the epineurium of the affected nerve. Conclusions Although it is rare, postoperative idiopathic neuropathy occurs in clinical practice, and it is crucial that surgeons recognize the existence of this neuropathy to elucidate its pathogenesis as well as to reduce the risk of litigation.

OBJECTIVES: Given the rising prevalence of cisplatin-induced peripheral neuropathy (CisIPN), investigations to alleviate its adverse effects are required. Oxidative stress and free radical development are essential pathways of CisIPN. Specifically, dexamethasone and citicoline are characterized by anti-inflammatory and antioxidant activities that might reduce CisIPN incidence and severity. The current study assessed the possible impacts of novel interventions, dexamethasone, and, citicoline on CisIPN. MATERIALS AND METHODS: Seventy-two male mice were randomly allocated into nine groups (n: 8/each group). Different doses of dexamethasone (7.5, 15, 30 mg/kg, i.p.), citicoline (10, 20, 40 mg/kg, i.p.), and the combination (dexamethasone 7.5 mg/kg + citicoline 10 mg/kg, i.p.) were injected in the first three days and one day before receiving cisplatin (2 mg/kg, i.p.). The tail-flick method was used for assessing nociception. Besides, malondialdehyde (MDA), interleukin-1 beta (IL-1β), tumor necrosis factor-α (TNF-α), total antioxidant capacity (TAC), and mice weight differences (ΔW) were measured. RESULTS: Different doses of dexamethasone and citicoline enhanced latency time (p

Significance. This review highlights the many intracellular processes generating reactive oxygen species (ROS) in the peripheral nervous system in the context of type 1 diabetes. The major sources ...

Shulman's disease (eosinophilic fasciitis) is a very rare autoimmune disorder with an unknown etiopathogenesis. During the initial period of disease, it usually causes limb and trunk edema followed by collagenous thickening of the subcutaneous fascia. Eosinophilia is a predominant laboratory finding during the initial phase of the disease and less prominent in the later phases. Patients may also present with arthritis, myositis, peripheral neuropathy, and rarely pleuropericarditis. Here, we are reporting a case of eosinophilic fasciitis presenting with vague constitutional symptoms, fever, and peripheral blood eosinophilia followed by rapidly evolving skin tightening with joint contractures and muscle stiffness, which misled the treating team toward Scleroderma and its overlap syndromes. The diagnosis was finally clinched by a full-thickness skin biopsy along with underlying fascia and muscle tissue from an effected area, with a gratifying treatment response to standard immune suppression.

Poly (ADP-Ribose) polymerase inhibitors (PARPi) have emerged as a targeted therapy in cancer treatment with promising results in various types of cancer. This work aims to investigate the profile of adverse drug reactions (ADRs) associated with PARPi through the reports provided by the Eudravigilance (EV) database. We also intend to analyze the potential association of peripheral neuropathy to PARPi. Data on individual case safety reports (ICSRs) were obtained by accessing the European spontaneous reporting system via the EV website. A total of 12,762 ICSRs were collected from the EV database. Serious cases of nervous system disorders were analyzed providing strong evidence that peripheral neuropathy was reported in a higher frequency in patients treated with niraparib. Most cases reported a not recovered/not resolved outcome and involved drug withdrawal. However, several studies suggest that PARPi attenuate chemotherapy-induced painful neuropathy. Unexpected ADRs such as peripheral neuropathy may also occur, mostly in patients taking niraparib. Further pharmacovigilance studies should be conducted in this area to clarify with more precision the toxicity profile of these drugs.

Paclitaxel is a chemotherapeutic agent used to treat a wide range of malignant tumors. Although it has anti-tumoral properties, paclitaxel also shows significant adverse effects on the peripheral nervous system, causing peripheral neuropathy. Paclitaxel has previously been shown to exert direct neurotoxic effects on primary DRG neurons. However, little is known about paclitaxel’s effects on non-neuronal DRG cells. They provide mechanical and metabolic support and influence neuronal signaling. In the present study, paclitaxel effects on primary DRG non-neuronal cells were analyzed and their concentration or/and time dependence investigated. DRGs of Wister rats (6–8 weeks old) were isolated, and non-neuronal cell populations were separated by the density gradient centrifugation method. Different concentrations of Paclitaxel (0.01 µM–10 µM) were tested on cell viability by MTT assay, cell death by lactate dehydrogenase (LDH) assay, and propidium iodide (PI) assay, as well as cell proliferation by Bromodeoxyuridine (BrdU) assay at 24 h, 48 h, and 72 h post-treatment. Furthermore, phenotypic effects have been investigated by using immunofluorescence techniques. Paclitaxel exhibited several toxicological effects on non-neuronal cells, including a reduction in cell viability, an increase in cell death, and an inhibition of cell proliferation. These effects were concentration- and time-dependent. Cellular and nuclear changes such as shrinkage, swelling of cell bodies, nuclear condensation, chromatin fragmentation, retraction, and a loss in processes were observed. Paclitaxel showed adverse effects on primary DRG non-neuronal cells, which might have adverse functional consequences on sensory neurons of the DRG, asking for consideration in the management of peripheral neuropathy.

Introduction: Peripheral neuropathy (PNP) in feet and/or hands and sexual dysfunction are common side effects of cancer therapies. In patients with other diseases, there is evidence of an association between peripheral nervous system disorders and sexual dysfunction due to the impact of impaired neuronal control on genital organ sensitivity. In cancer patient interviews, it has now been observed that PNP and sexual dysfunction may be related. The aim of the study was to investigate the potential association between PNP, sexual dysfunction, and physical activity behavior.Methods: Ninety-three patients with PNP of the feet and/or hands were interviewed in August/September 2020 in a cross-sectional study regarding medical history, sexual dysfunction and functionality of the genital organs.Results: Thirty-one persons who participated in the survey provided seventeen evaluable questionnaires (four men, thirteen women). Nine women (69%) and three men (75%) reported sensory disorders of the genital organs. Three men (75%) had erectile dysfunction. All men who had sensory symptoms of the genital organs received chemotherapy, and one man also received immunotherapy. Eight women were sexually active. Five (63%) of them reported genital organ symptoms and mainly lubrication disorders. Four (80%) of the five sexually inactive women reported genital organ symptoms. Eight of the nine women with sensory symptoms of the genital organs received chemotherapy, and one woman received immunotherapy. Discussion: Our limited data suggest genital organ sensory symptoms in chemotherapy and immunotherapy patients. Genital organ symptoms do not appear to be directly related to sexual dysfunction, and the association between PNP and genital organ symptoms appears to be more pronounced in sexually inactive women. Chemotherapy could cause sensory symptoms of the genital organs and sexual dysfunction by damaging genital organ nerve fibers. Chemotherapy and anti-hormone therapy (AHT) could trigger a disturbance of the hormone balance, which in turn could be causative for sexual dysfunction. It remains open whether the cause of these disorders is the symptomatology of the genital organs or the altered hormone balance. The significance of the results is limited due to the small number of cases. To our knowledge, this study is the first of its kind in cancer patients and allows a better understanding of the association between PNP, sensory symptoms of the genital organs, and sexual dysfunction. Conclusion: In order to be able to narrow down the cause of these initial observations in cancer patients more precisely, larger studies are needed that can relate the influence of cancer therapy-induced PNP, physical activity level and hormone balance to sensory symptoms of the genital organs and sexual dysfunction. The methodology of further studies should take into account the frequent problem of low response rates in surveys on sexuality. Einleitung: Polyneuropathie (PNP) in Füßen und/oder Händen und sexuelle Dysfunktion sind häufige Nebenwirkungen von Krebstherapien. Bei Patient*innen mit anderen Erkrankungen gibt es Hinweise auf einen Zusammenhang zwischen Erkrankungen des peripheren Nervensystems und der sexuellen Dysfunktion aufgrund des Einflusses der gestörten neuronalen Kontrolle auf die Sensibilität der Genitalorgane. In Gesprächen mit Krebspatient*innen wurde nun beobachtet, dass die PNP und die sexuelle Dysfunktion möglicherweise zusammenhängen. Ziel der Studie war, den potentiellen Zusammenhang zwischen PNP, sexueller Dysfunktion und körperlichem Aktivitätsverhalten zu untersuchen.Methoden: Dreiundneunzig Patient*innen mit PNP der Füße und/oder Hände wurden im August/September 2020 in einer Querschnittuntersuchung bezüglich Krankengeschichte, sexueller Dysfunktion und Funktionalität der Genitalorgane befragt.Ergebnisse: Einunddreißig Personen, die an der Umfrage teilnahmen, lieferten siebzehn auswertbare Fragebögen (vier Männer, dreizehn Frauen). Neun Frauen (69%) und drei Männer (75%) berichteten über Gefühlsstörungen an den Geschlechtsorganen. Drei Männer (75%) hatten eine erektile Dysfunktion. Alle Männer, die sensorische Beeinträchtigungen der Genitalorgane aufwiesen, erhielten Chemotherapie, und ein Mann zudem Immuntherapie. Acht Frauen waren sexuell aktiv. Fünf (63%) von ihnen berichteten von Symptomen der Genitalorgane und hauptsächlich Lubrikationsstörungen. Vier (80%) der fünf sexuell inaktiven Frauen berichteten von Symptomen der Genitalorgane. Acht der neun Frauen mit sensorischen Symptomen der Genitalorgane erhielten Chemotherapie und eine Frau erhielt Immuntherapie.Diskussion: Unsere begrenzten Daten deuten auf sensorische Symptome der Genitalorgane bei Chemotherapie- und Immuntherapie-Patient*innen hin. Symptome der Genitalorgane scheinen nicht direkt mit sexueller Dysfunktion zusammenzuhängen und der Zusammenhang zwischen PNP und Symptomen der Genitalorgane scheint bei sexuell inaktiven Frauen ausgeprägter zu sein. Chemotherapie könnte durch Schädigung von Nervenfasern der Genitalorgane sensorische Symptome im Genitalbereich und eine sexuelle Dysfunktion verursachen. Chemotherapie und Anti-Hormontherapie (AHT) könnten eine Störung des Hormonhaushaltes auslösen, die wiederum ursächlich für eine sexuelle Dysfunktion sein könnte. Es bleibt offen, ob eine Symptomatik an den Genitalorganen oder der veränderte Hormonhaushalt Ursache dieser Störungen ist. Die Aussagekraft der Ergebnisse ist aufgrund der geringen Fallzahl eingeschränkt. Diese Untersuchung ist nach unserer Kenntnis die erste dieser Art bei Krebspatient*innen und ermöglicht ein besseres Verständnis für den Zusammenhang von PNP, sensorischen Symptomen der Genitalorgane und sexueller Dysfunktion. Fazit: Um die Ursache dieser ersten Beobachtungen bei Krebspatient*innen genauer eingrenzen zu können, sind größere Studien notwendig, die den Einfluss der Krebstherapie-induzierten PNP, des körperlichen Aktivitätsniveaus und des Hormonhaushalts auf die sensorischen Symptome der Genitalorgane und die sexuelle Dysfunktion in Beziehung setzen können. Bei der Methodik weiterer Studien sollte das häufig auftretende Problem der geringen Rücklaufquoten in Befragungen zur Sexualität berücksichtigt werden.

Regular physical activity is an important component of diabetes management. However, there are limited data on the habitual physical activity of people with or at risk of diabetes-related foot complications. The aim of this study was to describe the habitual physical activity of people with or at risk of diabetes-related foot complications in regional Australia. Twenty-three participants with diabetes from regional Australia were recruited with twenty-two participants included in subsequent analyses: no history of ulcer (N = 11) and history of ulcer (N = 11). Each participant wore a triaxial accelerometer (GT3X+; ActiGraph LLC, Pensacola, FL, USA) on their non-dominant wrist for 14 days. There were no significant differences between groups according to both participant characteristics and physical activity outcomes. Median minutes per day of moderate-to-vigorous physical activity (MVPA) were 9.7 (IQR: 1.6–15.7) while participants recorded an average of 280 ± 78 min of low-intensity physical activity and 689 ± 114 min of sedentary behaviour. The sample accumulated on average 30 min of slow walking and 2 min of fast walking per day, respectively. Overall, participants spent very little time performing MVPA and were largely sedentary. It is important that strategies are put in place for people with or at risk of diabetes-related foot complications in order that they increase their physical activity significantly in accordance with established guidelines.

Background: Peripheral neuropathy (PN) is a debilitating complication among colorectal cancer (CRC) survivors that can become chronic. No large-scale study has yet analyzed correlates in multivariable models. We did multivariable analyses to find correlates of PN. Methods: In 1,516 all-stage Dutch CRC survivors, cross-sectional data were collected on sensory, motor, autonomic, and total PN, sociodemographic (age, sex, education, employment, partner), clinical (time since diagnosis, tumor location, stage, chemotherapy, radiotherapy, comorbidities), lifestyle (alcohol, smoking, physical activity, body mass index), psychological factors (anxiety, depression, personality), and health-related quality of life (HRQoL). After multiple imputations, correlates were analyzed with linear regressions and eliminated with backward selection. Results: CRC survivors (69 years; 42% female) were on average 5 years post-diagnosis, and 28%–65% reported PN. PN was associated with older age, being male (sensory) or female (motor), shorter time since diagnosis, chemotherapy, comorbidities, anxiety, depression, and worse scores on HRQoL domains, and pain, nausea, vomiting, insomnia, constipation, and financial problems. Conclusions: In multivariable analyses, PN is affected by receiving chemotherapy, aging, sex, comorbidities, stress-related factors, and HRQoL in CRC survivors. Future PN-related studies can include these factors, and they can be examined in longitudinal studies to gain more knowledge about chronicity and severity of PN.

Movement disorders as well as peripheral neuropathies are extremely frequent in the general population; therefore, it is not uncommon to encounter patients with both these conditions. Often, the coexistence is coincidental, due to the high incidence of common causes of peripheral neuropathy, such as diabetes and other age-related disorders, as well as of Parkinson disease (PD), which has a typical late onset. Nonetheless, there is broad evidence that PD patients may commonly develop a sensory and/or autonomic polyneuropathy, triggered by intrinsic and/or extrinsic mechanisms. Similarly, some peripheral neuropathies may develop some movement disorders in the long run, such as tremor, and rarely dystonia and myoclonus, suggesting that central mechanisms may ensue in the pathogenesis of these diseases. Although rare, several acquired or hereditary causes may be responsible for the combination of movement and peripheral nerve disorders as a unique entity, some of which are potentially treatable, including paraneoplastic, autoimmune and nutritional aetiologies. Finally, genetic causes should be pursued in case of positive family history, young onset or multisystemic involvement, and examined for neuroacanthocytosis, spinocerebellar ataxias, mitochondrial disorders and less common causes of adult-onset cerebellar ataxias and spastic paraparesis. Deep phenotyping in terms of neurological and general examination, as well as laboratory tests, neuroimaging, neurophysiology, and next-generation genetic analysis, may guide the clinician toward the correct diagnosis and management.

Objectives Neurological complications including pain are common after treatment for breast cancer. This prospective study investigated the symptoms, intensity and interference of chemotherapy-induced peripheral neuro-pathy. (CIPN) in the feet and hands compared to surgery- and radiation-induced neuropathy in the breast and upper arm. Methods Consecutive patients referred to surgery for breast cancer were included in a prospective study and completed a questionnaire at baseline and a follow-up questionnaire and interview after one year. CIPN was assessed with the CIPN20 questionnaire and the Michigan Neuropathy Screening Instrument questionnaire (MNSIq). Pain intensity was rated on a numeric rating scale (NRS, 0–10). Results In total 144 patients were included, of which 73 received chemotherapy. At one-year follow-up, symptoms of polyneuropathy were more common in patients treated with chemotherapy. Tingling or numbness in the feet in those treated/not treated with chemotherapy was reported by 44 (62%) and 15 (21%), respectively. Pain was present in 22 (30%) and 10 (14%), respectively. Pain in the area of surgery was reported by 66 (46%). Although less common, pain in the feet in those treated with chemotherapy was rated as more intense and with more daily life interference than pain in the surgical area (NRS 5.5 (SD 1.9) vs. 3.1 (SD 1.9). Conclusions Neurological complications including pain following surgery and chemotherapy represent a burden to breast cancer survivors. In those who had received chemotherapy, pain in the feet was less common than pain in the surgical area, but pain in the feet was more intense and had a higher interference with daily life. Our study emphasizes the need for either baseline data or a control population for improved estimation of the presence and severity of CIPN and pain from questionnaires.

Purpose Previous evidence regarding the impact of exercise interventions on chemotherapy-induced peripheral neuropathy often focuses on lower-extremity functions, such as muscle strength and balance ability, while their efects on upper extremities remain unknown. We aimed to evaluate the efcacy of combined hand exercise intervention on upper-extremity function, symptoms, and quality-of-life in patients with chemotherapy-induced peripheral neuropathy (CIPN). Methods After screening 341 patients, 42 were randomly assigned to either the intervention (n=21) or control (n=21) group. Participants were evaluated at baseline (T0) and after one (T1) and two (T2) chemotherapy cycles. The primary outcome was upper-extremity function measured using the Michigan Hand Outcomes Questionnaire (MHQ) at T2. The intention-to-treat and as-treated populations were compared using a mixed-efect model. Results In the intention-to-treat analysis, the decline in activities of daily living of MHQ was signifcantly suppressed in the intervention group compared with that in the control group at T2 (diference: 7.23; 95% confdence interval: 0.35–14.10). Similarly, in the as-treated analysis, the decline in activities of daily living of MHQ was signifcantly suppressed in the intervention group compared with that in the control group at T2 (diference: 13.09; 95% confdence interval: 5.68–20.49). Pain also signifcantly improved in the intervention group compared with that in the control group at T2 (diference: 13.21; 95% confdence interval:−22.91 to−3.51). Conclusion The combined hand exercise intervention may improve upper-extremity function, such as by suppressing decline in ADL, and reduce pain in patients with CIPN., 長崎大学学位論文 学位記番号:博(医歯薬)甲第1459号 学位授与年月日:令和4年6月1日, Author: Yuta Ikio, Akira Sagari, Akira Nakashima, Daiki Matsuda, Terumitsu Sawai, Toshio Higashi, Citation: Supportive Care in Cancer, 30, pp.4981-4992; 2022

Altered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain reported in many of these disorders. Here, we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification. Ninety-seven percent of these patients carry an R206H gain-of-function point mutation in the BMP type I receptor ACVR1 (ACVR1 R206H ), which causes neofunction to Activin A and constitutively activates signaling through phosphorylated SMAD1/5/8. Although patients with FOP can harbor pathological lesions in the peripheral and central nervous system, their etiology and clinical impact are unclear. Quantitative sensory testing of patients with FOP revealed significant heat and mechanical pain hypersensitivity. Although there was no major effect of ACVR1 R206H on differentiation and maturation of nociceptive sensory neurons (iSNs) derived from FOP induced pluripotent stem cells, both intracellular and extracellular electrophysiology analyses of the ACVR1 R206H iSNs displayed ACVR1-dependent hyperexcitability, a hallmark of neuropathic pain. Consistent with this phenotype, we recorded enhanced responses of ACVR1 R206H iSNs to TRPV1 and TRPA1 agonists. Thus, activated ACVR1 signaling can modulate pain processing in humans and may represent a potential target for pain management in FOP and related BMP pathway diseases.

Purpose The purpose of this study was to investigate the effectiveness of photobiomodulation (PBM) therapy for the prevention of chemotherapy-induced peripheral neuropathy (CIPN) in breast cancer patients. Methods A prospective, randomized placebo-controlled pilot trial (NEUROLASER) was set up with 32 breast cancer patients who underwent chemotherapy (ClinicalTrials.gov; NCT03391271). Patients were randomized to receive PBM (n = 16) or placebo treatments (n = 16) (2 × /week) during their chemotherapy. The modified Total Neuropathy Score (mTNS), six-minute walk test (6MWT), Numeric pain Rating Scale (NRS), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Taxane (FACT/GOG-Taxane) were used to evaluate the severity of CIPN and the patients’ quality of life (QoL). Outcome measures were collected at the first chemotherapy session, 6 weeks after initiation of chemotherapy, at the final chemotherapy session, and 3 weeks after the end of chemotherapy (follow-up). Results The mTNS score increased significantly over time in both the control and the PBM group. A significantly higher score for FACT/GOG-Taxane was observed in the PBM group during chemotherapy compared to the control group. Questions of the FACT/GOG-Taxane related to sensory peripheral neuropathy symptoms showed a significant increase in severeness over time in the control group, whereas they remained constant in the PBM group. At follow-up, a (borderline) significant difference was observed between both groups for the 6MWT and patients’ pain level, in benefit of the PBM group. Conclusions This NEUROLASER trial shows promising results concerning the prevention of CIPN with PBM in breast cancer patients. Furthermore, a better QoL was observed when treated with PBM.

BACKGROUND: The increasing colorectal cancer (CRC) survivor population highlights the need for dietary recommendations in order to enhance health-related quality of life (HRQoL) and alleviate symptoms of fatigue, chemotherapy-induced peripheral neuropathy (CIPN) and gastro-intestinal problems.OBJECTIVES: Because of the therapeutic potential of dietary fiber on the gut, we aim to assess longitudinal associations of post-diagnostic dietary fiber, fruit and vegetable intake, a major source of dietary fiber, with HRQoL, fatigue, CIPN and gastro-intestinal symptoms in CRC survivors from 6 weeks to 24 months post-treatment.METHODS: In a prospective cohort among stage I-III CRC survivors (n = 459), five repeated study measurements between diagnosis and 24 months post-treatment were executed. Dietary fiber and fruit and vegetable intake were measured by 7-day dietary records. HRQoL, fatigue, CIPN and gastro-intestinal symptoms were measured by validated questionnaires. We applied confounder-adjusted linear mixed-models to analyze longitudinal associations from 6 weeks until 24 months post-treatment, and used hybrid models to disentangle the overall association into intra-individual changes and inter-individual differences over time.RESULTS: Higher dietary fiber intake, fruit and vegetable intake were longitudinally associated with statistically significant better physical functioning and less fatigue. Intra-individual analyses showed that an increase of 10 g/d in dietary fiber within individuals over time was associated with better physical functioning (β: 2.3; 95% CI: 0.1, 4.4), role functioning (ability to perform daily activities - 5.9; 1.5, 10.3), and less fatigue (-4.1; -7.7,-0.5). An average increase in fruit and vegetable intake of 100 g/d between individuals over time was predominantly associated with less fatigue (-2.2; -4.2,-0.3). No associations were found with CIPN and gastro-intestinal symptoms.CONCLUSION: Our results suggest that increasing dietary fiber, fruit and vegetable intake is related to better physical and role functioning and less fatigue in the first two years after the end of treatment for CRC.Registration: The EnCoRe study was registered at trialregister.nl as NL6904 (former ID: NTR7099).

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is probably the best-recognised progressive immune-mediated peripheral neuropathy. It presents with symmetrical, motor predominant peripheral neuropathy that produces both distal and proximal weakness. Here we report a case of a 38-year-old man who presented with chronic additive large and small joint inflammatory polyarthritis, associated with morning stiffness, anasarca associated with frothy urine and progressive episodic, relapsing and remitting, sensorimotor lower motor neuron type quadriparesis without any bladder and bowel involvement. He was diagnosed as a case of CIDP, and the aetiology was found out to be mixed connective tissue disorder, which is a rare association with CIDP. The patient responded dramatically to glucocorticoid.

Although widely studied, the association between migraines (M) and breast cancer (BC) risk remains evasive. In this prospective single-center study, 440 early or locally advanced BC patients were enrolled at IRCCS Humanitas Research Hospital. Clinical and demographical data were collected. Those who suffered from headaches were evaluated with the International Classification of Headache Disorders. M was found to be significantly more prevalent in BC patients: 56.1% versus an expected prevalence of 17% in the global population. M patients showed a higher risk of having stage II or III BC than stage I, which was more frequently found in the non-headache population. Interestingly, the frequency of headache attacks was positively correlated with estrogen (r = 0.11, p = 0.05) and progesterone (r = 0.15, p = 0.007) expression, especially in patients with migraine without aura. The higher the expression of hormone receptors in BC, the higher the headache frequency. Moreover, patients suffering from headaches showed an overall earlier onset of BC. Our findings challenge the idea of a net preventive role of M on BC, suggesting a rather complex interaction in which M mostly influences some BC subtypes and vice versa. Further multi-center studies with extended follow-up are needed.

This 18-year-old boy presented to the hospital with symptoms of cerebellar dysfunction preceded by an acute febrile illness with rash. Examination showed evidence of left-sided cerebellar dysfunction and polyneuropathy. Empirical treatment for leptospirosis and scrub typhus was initiated. MRI was normal. Other organ dysfunctions in the form of thrombocytopenia and transaminitis were also observed. He recovered without sequelae. A diagnosis of acute cerebellar ataxia and polyneuropathy due to scrub typhus was made.

Diabetes mellitus may for the first time present with its classical features or with long term complications which may or may not be recognised. Knowledge of diabetes mellitus and its complications, sociocultural beliefs and perception, patronage of traditional healers may influence time of presentation and hence, outcomes. We report the case of a female Nigerian food vendor, who was admitted in coma and managed for septic left-hand ulcer and incidental diabetes mellitus. She had painless peripheral neuropathy, which gave her the ''ability'' to handle hot objects. This was misconstrued as some special gift derived from a benevolent spirit, until she sustained thermal injury and a non-healing wound on her left hand. She presented to a traditional healer which delayed hospital presentation. She was eventually brought to hospital in coma and related diabetes mellitus was found. She was appropriately managed for hyperglycaemic coma and sepsis as well as wound care and was discharged to the out patients' services on appropriate drugs and life style measures.

Charcot–Marie–Tooth disease (CMT) is a group of inherited peripheral nerve disorders characterized by progressive muscle weakness and atrophy, sensory loss, foot deformities and steppage gait. Missense mutations in the gene encoding the small heat shock protein HSPB8 (HSP22) have been associated with hereditary neuropathies, including CMT. HSPB8 is a member of the small heat shock protein family sharing a highly conserved α-crystallin domain that is critical to its chaperone activity. In this study, we modeled HSPB8 mutant-induced neuropathies in Drosophila. The overexpression of human HSPB8 mutants in Drosophila neurons produced no significant defect in fly development but led to a partial reduction in fly lifespan. Although these HSPB8 mutant genes failed to induce sensory abnormalities, they reduced the motor activity of flies and the mitochondrial functions in fly neuronal tissue. The motor defects and mitochondrial dysfunction were successfully restored by PINK1 and parkin, which are Parkinson’s disease-associated genes that have critical roles in maintaining mitochondrial function and integrity. Consistently, kinetin riboside, a small molecule amplifying PINK1 activity, also rescued the loss of motor activity in our HSPB8 mutant model.

Complex orofacial pain disorders, such as trigeminal neuralgia (TN) and atypical facial pain (AFP), can be excruciating and debilitating during attacks. Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, is a powerful analgesic that has been used to treat various chronic pain conditions, but its role in treating complex facial pain has only been recently explored. In this retrospective case series, we reviewed the efficacy of continuous ketamine infusion for 12 patients with facial pain refractory to medical treatment. Patients who presented with a diagnosis of TN were more likely to have significant and sustained pain relief after receiving ketamine infusion. By contrast, those who did not respond to the treatment were more likely to have a diagnosis of AFP. The current report suggests a fundamental difference between these two facial pain disorders in their respective underlying pathophysiology and supports the use of continuous ketamine infusion for refractory TN, but not AFP.

BackgroundDespite the primary myelin-related pathophysiology, small fiber neuropathy (SFN) and axonal degeneration are also considered to be involved and associated with disabling symptoms and impaired quality of life in chronic inflammatory demyelinating polyneuropathy (CIDP). Demonstration of SFN usually requires complex or invasive investigations.ObjectsIn vivo corneal confocal microscopy (IVCCM) has evolved as a non-invasive, easily applied method for quantification of small fiber involvement in peripheral nerve disorders. We aimed to investigate the potential role of IVCCM in CIDP.MethodsIn this cross-sectional study, 15 patients with CIDP underwent assessment with clinical disability scales, neuropathic pain (NP) and autonomic symptom questionnaires, nerve conduction studies, and IVCCM. IVCCM parameters were analyzed and compared to those from 32 healthy controls.ResultsCorneal nerve fiber density (CNFD) and corneal nerve fiber length (CNFL) were significantly decreased in the CIDP group, compared to those in controls (p = 0.03 and p = 0.024, respectively). Langerhans cells and fiber tortuosity were increased in CIDP patients (p = 0.005 and p = 0.001, respectively). IVCCM parameters were significantly lower in patients with NP compared to those in patients without NP.ConclusionIVCCM shows promise as a non-invasive complementary biomarker in the assessment of demyelinating polyneuropathies, providing insights into the potential pathophysiology of these non-length-dependent neuropathies.

A 23-year-old previously healthy male was referred to the clinical neurophysiology unit due to a relatively fast-onset paralysis of muscles of the anterior right leg. Electroneuromyography (ENMG) revealed a total denervation of the muscles innervated by the deep peroneal nerve, diminished sensory response of the superficial peroneal nerve, and partial denervation of the peroneus longus muscle. Ultrasound and magnetic resonance imaging (MRI) revealed a large fluid collection inside the common peroneal nerve, primarily suspected to be an intraneural ganglion cyst. The cyst was surgically excised, and the function of the muscles innervated by the peroneal nerve was recovering at the control ENMG 6 months later. We describe a case of a large intraneural ganglion cyst of the peroneal nerve in an otherwise healthy young male, diagnosis by ENMG, ultrasound, and MRI, as well as subsequent operative treatment. This report demonstrates the utility of nerve ultrasound in differentiating between different causes of peroneal nerve dysfunction.

We herein report a case of myoclonic epilepsy with ragged-red fibers (MERRF) harboring a novel variant in mitochondrial cysteine transfer RNA (MT-TC). A 68-year-old woman presented with progressive myoclonic epilepsy with optic atrophy and peripheral neuropathy. A skin biopsy revealed p62-positive intranuclear inclusions. No mutations were found in the causative genes for diseases known to be related to intranuclear inclusions; however, a novel variant in MT-TC was found. The association between intranuclear inclusions and this newly identified MERRF-associated variant is unclear; however, the rare complication of intranuclear inclusions in a patient with typical MERRF symptoms should be noted for future studies.

Gut dysbiosis, defined as pathogenic alterations in the distribution and abundance of different microbial species, is associated with neuropathic pain in a variety of clinical conditions, but this has not been explored in the context of neuropathy in people with HIV (PWH). We assessed gut microbial diversity and dysbiosis in PWH and people without HIV (PWoH), some of whom reported distal neuropathic pain (DNP). DNP was graded on a standardized, validated severity scale. The gut microbiome was characterized using 16S rRNA sequencing and diversity was assessed using phylogenetic tree construction. Songbird analysis (https://github.com/mortonjt/songbird) was used to produce a multinomial regression model predicting counts of specific microbial taxa through metadata covariate columns. Participants were 226 PWH and 101 PWoH, mean (SD) age 52.0 (13.5), 21.1% female, 54.7% men who have sex with men, 44.7% non-white. Among PWH, median (interquartile range, IQR) nadir and current CD4 were 174 (21, 302) and 618 (448, 822), respectively; 90% were virally suppressed on antiretroviral therapy. PWH and PWoH did not differ with respect to microbiome diversity as indexed by Faith's phylogenetic diversity (PD). More severe DNP was associated with lower alpha diversity as indexed by Faith's phylogenetic diversity in PWH (Spearman's ρ=.224, P=0.0007), but not in PWoH (Spearman's ρ=.032, P=.748). These relationships were not confounded by demographics or disease factors. In addition, the log-ratio of features identified at the genus level as Blautia to Lachnospira was statistically significantly higher in PWH with DNP than in PWH without DNP (t-test, P=1.01e-3). Furthermore, the log-ratio of Clostridium features to Lachnospira features also was higher in PWH with DNP than in those without (t-test, P=6.24e-5). Our results, in combination with previous findings in other neuropathic pain conditions, suggest that gut dysbiosis, particularly reductions in diversity and relative increases in the ratios of Blautia and Clostridium to Lachnospira, may contribute to prevalent DNP in PWH. Two candidate pathways for these associations, involving microbial pro-inflammatory components and microbially-produced anti-inflammatory short chain fatty acids, are discussed. Future studies might test interventions to re-establish a healthy gut microbiota and determine if this prevents or improves DNP. PERSPECTIVE: The association of neuropathic pain in people with HIV with reduced gut microbial diversity and dysbiosis raises the possibility that re-establishing a healthy gut microbiota might ameliorate neuropathic pain in HIV by reducing proinflammatory and increasing anti-inflammatory microbial products.

HIV is one of the most important risk factors of tuberculosis (TB)-related morbidity and mortality. Isoniazid preventive therapy (IPT) is recommended to prevent latent TB reactivation in patients with HIV. However, due to multiple therapies and comorbidities, these patients are predisposed to adverse drug reactions (ADRs) that lead to increased morbidity and mortality. The aim of this study was to determine the prevalence and associated factors of suspected IPT-linked ADRs in HIV-positive patients using IPT.A cross-sectional study was conducted between February and March 2020 at 3 regional referral hospitals (RRHs) in central Uganda. We sampled 660 HIV-positive patients aged 10 years or older who received IPT between July and December 2019 inclusive. Patients were interviewed using a pretested structured questionnaire, and their treatment records were reviewed. A modified Poisson regression model with clustered robust standard errors was used to identify factors associated with suspected IPT-linked ADRs.The prevalence of the suspected ADRs was 51% (334 of the 660; 95% confidence interval [CI]: 18% to 83%). Patients self-reported 7-fold the number of suspected ADRs documented in the clinical files by the health care workers. Musculoskeletal symptoms were the most frequently experienced reaction (14%), followed by dizziness (13%) and peripheral neuropathy (11%). Serious suspected ADRs were experienced by 12% of the study participants; the most common were hepatotoxicity (26%), dizziness (23%), and neuropathy (17%). Female sex (aPR [adjusted prevalence ratio]: 0.92, 95% CI: = 0.88 to 0.95), study site (aPR: 1.09, 95% CI: = 1.09 to 1.18), level of education (aPR: 0.94, 95% CI: = 0.94 to 0.99), history of TB (aPR: 0.93, 95% CI: = 0.87 to 0.99), good IPT adherence (aPR: 1.16, 95% CI: = 1.05 to 1.29), and use of protease inhibitor (PI)-based antiretroviral therapy (aPR: 1.01, 95% CI: = 1.00 to 1.02) were significantly associated with suspected IPT-linked ADRs.The prevalence of suspected IPT-linked ADRs is high, and hepatotoxicity is the most commonly reported serious suspected ADR. Patients self-reported more suspected ADRs than those documented in clinical files by health care workers. Patient engagement could improve ADR detection and potentially strengthen the pharmacovigilance system. Patients with a high risk of ADR ought to be monitored regularly to enable early detection and management.

Background: It is unclear whether glycemic variability (GV) is a risk factor for diabetic peripheral neuropathy (DPN), and whether control of GV is beneficial for DPN. The purpose of this study was to investigate the effect of GV on peripheral nerve damage by inducing glucose fluctuation in streptozotocin-induced diabetic rats.Methods: Rats were divided into four groups: normal (normal glucose group [NOR]), diabetes without treatment (sustained severe hyperglycemia group; diabetes mellitus [DM]), diabetes+once daily insulin glargine (stable hyperglycemia group; DM+LAN), and diabetes+once daily insulin glargine with twice daily insulin glulisine (unstable glucose fluctuation group; DM+Lantus [LAN]+Apidra [API]). We measured anti-oxidant enzyme levels and behavioral responses against tactile, thermal, and pressure stimuli in the plasma of rats. We also performed a quantitative comparison of cutaneous and sciatic nerves according to glucose fluctuation.Results: At week 24, intraepidermal nerve fiber density was less reduced in the insulin-administered groups compared to the DM group (P0.05; 16.2±1.6, 12.4±2.0, 14.3±0.9, and 13.9±0.6 for NOR, DM, DM+LAN, and DM+LAN+API, respectively). The DM group exhibited significantly decreased glutathione levels compared to the insulin-administered groups (2.64±0.10 μmol/mL, DM+LAN; 1.93±0.0 μmol/mL, DM+LAN+API vs. 1.25±0.04 μmol/mL, DM; P

Актуальність. Синдром Гійена — Барре (СГБ) при запальних хворобах суглобів описується у вигляді поодиноких спостережень, і багато клініко-патогенетичних аспектів такої периферійної нейропатії (ПНП) залишаються нез’ясованими. Мета дослідження: оцінити частоту й характер перебігу СГБ при ревматоїдному артриті (РА), реактивному хламідійному урогенітальному артриті (РеА), псоріатичному артриті (ПА) та анкілозуючому спондиліті (АС), вивчити патогенетичні побудови цієї нейропатії, виділити чинники ризику. Матеріал і методи. Під спостереженням перебували 416 пацієнтів із запальними захворюваннями суглобів, серед яких був 131 хворий на РА, 101 — на РеА, 76 — на ПА і 108 — на АС. Середній вік цих обстежених відповідно склав 45, 32, 42 і 38 років, тривалість захворювання — 10, 4, 12 і 11 років, а співвідношення чоловіків та жінок — 1 : 5, 1 : 1, 1 : 2 і 10 : 1. Результати. СГБ розвивається відповідно у 3, 4, 5 і 9 % від загального числа хворих із РА, ПА, РеА й АС, або в 24, 17, 26 і 27 % від числа таких пацієнтів із ПНП, що тісно пов’язано з наявністю при всіх захворюваннях тендовагінітів та з тяжкістю перебігу суглобового синдрому, при РА залежить від дигітального артеріїту, гіпофункції щитоподібної залози і синдрому Шегрена, при РеА — від порушень збудливості міокарда й електричної провідності серця, при ПА — ексудативної форми шкірного псоріазу, при АС — остеопорозу, а в патогенезі СГБ беруть участь імунні порушення, процеси ендотеліальної дисфункції судин та зміни фізико-хімічних адсорбційно-реологічних в’язкоеластичних й релаксаційних властивостей крові. Висновки. СГБ взаємопов’язаний із клініко-лабораторними ознаками запальних захворювань суглобів, а в майбутньому буде корисним активне виявлення такої патології нервової системи задля подальших своєчасних реабілітаційних заходів, причому серопозитивність артритів за антитілами до циклічного цитрулінового пептиду є чинником ризику такої ПНП.

Relevance. Peripheral neuropathy (PNP) in urogenital chlamydia reactive arthritis (CRA) is described as single observations, and many clinical and pathogenetic aspects of this lesion of the nervous system remain unclear. Objective of the study: to evaluate the incidence and nature of the clinical course of PNP in CRA, the connection of the nerve and joint injuries, to explore the questions of pathogenetic constructions of this neuropathy, to identify risk factors. Material and methods. We observed 101 patients with CRA, mean age of them was 32 years, disease duration — 4 years, and the male to female ratio — 1 : 1. In 90 % of CRA cases, Chlamydia trochamatis was found in prostatic secretions, in scraps from the urethra, the cervix, the vaginal wall, in 83 % — positive serologic tests for chlamydia infection. Results. Signs of PNP in CRA were in 19 % of patients in the ratio of mononeuropathy to polyneuropathy as 1 : 1, with motor, sensory and mixed disorders in a ratio of 1 : 3 : 6, the presence of autonomic changes in every second patient and more frequent distal localization of the process in the hands, which is influenced by the severity of the articular syndrome, high levels of antichlamydia antibodies in the blood, and the axonal and demyelinating indicators of electroneuromyography — by the severity of urogenital lesions and the presence of Guillain-Barre syndrome. A high rate of arthritis progression is a prognosis-negative sign of PNP course in patients with CRA. The pathogenic constructions of PNP involve the inflammatory immune proteins, disturbances of vascular endothelial function and physicochemical surface rheological pro­perties of the serum. Conclusion. PNP takes place in every fifth patient with CRA, correlates with clinical and laboratory signs of joint disease, and in the future will be useful to identify actively this pathology of the nervous system for the subsequent timely rehabilitation, and CRA seropositivity for cyclic citrullinated peptide antibodies is a risk factor for such PNP.

INTRODUCTION: Chemotherapy-induced peripheral neurotoxicity (CIPN) remains a significant toxicity in cancer survivors without preventative strategies or rehabilitation. Exercise and physical activity-based interventions have demonstrated promise in reducing existing CIPN symptoms and potentially preventing toxicity, however there is a significant gap in evidence due to the lack of quality clinical trials and appropriate outcome measures. AREAS COVERED: The authors systematically reviewed outcome measures in CIPN exercise and physical rehabilitation studies with expert panel consensus via the Peripheral Nerve Society Toxic Neuropathy Consortium to provide recommendations for future trials. Across 26 studies, 75 outcome measures were identified and grouped into 16 domains within three core areas - measures of manifestations of CIPN (e.g. symptoms/signs), measures of the impact of CIPN and other outcome measures. EXPERT OPINION: This article provides a conceptual framework for CIPN outcome measures and highlights the need for definition of a core outcome measures set. The authors provide recommendations for CIPN exercise and physical rehabilitation trial design and outcome measure selection. The development of a core outcome measure set will be critical in the search for neuroprotective and treatment approaches to support cancer survivors and to address the significant gap in the identification of effective rehabilitation and treatment options for CIPN.

We examined the role of ATP and high mobility group box 1 (HMGB1) in paclitaxel-induced peripheral neuropathy (PIPN). PIPN in mice was prevented by HMGB1 neutralization, macrophage depletion, and P2X7 or P2X4 blockade. Paclitaxel and ATP synergistically released HMGB1 from macrophage-like RAW264.7 cells, but not neuron-like NG108-15 cells. The paclitaxel-induced HMGB1 release from RAW264.7 cells was accelerated by co-culture with NG108-15 cells in a manner dependent on P2X7 or P2X4. Paclitaxel released ATP from NG108-15 cells, but not RAW264.7 cells. Thus, PIPN is considered to involve acceleration of HMGB1 release from macrophages through P2X7 and P2X4 activation by neuron-derived ATP.

Pancreatic cancer (PC) is a lethal disease where most tumors are too advanced at diagnosis for resection, leaving chemotherapy as the mainstay of treatment. Although the prognosis of unresectable PC is poor, it has been dramatically improved by new chemotherapy treatments, such as the combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel. However, as oxaliplatin and paclitaxel are common neurotoxic drugs, chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe adverse effect of both treatments. As there are no agents recommended in the ASCO guidelines, we review the methods used to treat CIPN caused by PC treatment. The efficacy of duloxetine was observed in a large randomized controlled trial (RCT). In addition, pregabalin was more effective than duloxetine for CIPN in two RCTs. Although duloxetine and pregabalin can be effective for CIPN, they have several side effects. Therefore, the choice between the two drugs should be determined according to effect and tolerability. Mirogabalin is also used in patients with PC and there is hope it will yield positive outcomes when treating CIPN in the future.

Introduction: Thalidomide is an old well-known drug firstly used as morning sickness relief in pregnant women and then withdrawn from the market due to its severe side effects on fetal normal development. However, over the last few decades, the interest in this old drug has been renewed because of its efficacy in several important disorders as, for instance, multiple myeloma, breast cancer, and HIV-related diseases due to its antiangiogenic and immunomodulatory properties. Unfortunately, even in these cases, many after effects as deep vein thrombosis, peripheral neuropathy, constipation, somnolence, pyrexia, pain, and teratogenicity have been reported showing the requirement of careful and monitored use. For this reason, research efforts are geared toward the synthesis and optimization of new thalidomide analogues lacking in toxic effects, able to erase these limits and improve the pharmacological profile. Aims: This review aims to examine the state-of-the-art concerning the current studies on thalidomide and its analogues towards cancer diseases focusing the attention on the possible mechanisms of action involved and the lack of toxicity. Conclusion: In the light of the collected data, thalidomide analogues and their ongoing optimization could lead, in the future, to the realization of a promising therapeutic alternative for fighting cancer.

Ahmed Esmat,1 Mahmoud I Elshamy,2 Doaa Mohamed Zakaria,3 Zakarya Shady,4 Eman Roshdy Mohamed,3 Nashwa El-Khouly,3 Marwa M Hassan,3 Fatma M El-Senosy3 1Department of Neurology, Al-Azhar University, Faculty of Medicine, Cairo, Egypt; 2Department of Radiology, Al-Azhar University, Faculty of Medicine, Cairo, Egypt; 3Department of Internal Medicine, Faculty of Medicine (Girls), Al-Azhar University, Cairo, Egypt; 4Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, EgyptCorrespondence: Zakarya Shady Tel +201001281304Email zakaryashady96@yahoo.comPurpose: Diabetes is a documented risk factor for peripheral neuropathy. It was reported that associated hypertension could increase this risk. The present study aimed to assess the effect of hypertension and diabetes on median nerve using high-resolution ultrasound.Methods: The study includes 50 hypertensive patients (HTN group), 50 diabetic patients (DM group), 50 patients with coexisting diabetes and hypertension (HTN + DM group) and 50 healthy controls. Median nerve affection in the studied groups was studied by vibration perception thresholds (VPT). The median nerve cross-sectional area was determined at the nerve cross-sectional area of the median nerve at the carpal tunnel by high-resolution ultrasound. Clinical symptoms were assessed using Toronto Clinical Severity Score (TCSS).Results: There was significantly higher median nerve CSA in all patient groups in comparison to controls. HTN + DM group had significantly higher median nerve CSA when compared with DM group. Patients with peripheral neuropathy in HTN + DM and DM groups had significantly higher median nerve CSA than patients without. Using ROC curve analysis, it was shown that median CSA could successfully distinguish patients with peripheral neuropathy from patients without in HTN + DM group [AUC (95% CI): 0.71 (0.54– 0.89)] and in DM group [AUC (95% CI): 0.86 (0.72– 0.99)].Conclusion: Hypertensive patients with and without diabetes have significantly higher median nerve CSA when compared with controls.Keywords: hypertension, peripheral neuropathy, high-resolution ultrasound, diabetes mellitus, median nerve

Background Niemann–Pick is a rare metabolic disease distinguished by lysosomal storage defects. This disease is characterized by sphingomyelinase acid deficiency, causing its accumulation in various organs such as the kidneys, spleen, liver, brain, and nerves. Niemann–Pick disease is categorized into four groups: A, B, C, and D. Peripheral neuropathy is an extremely rare complication in patients with Niemann–Pick type C, which certainly leads to neurologic deterioration. Case presentation We report a case of Niemann–Pick type C disease in a 3-year-old Iranian Azeri female patient who was hospitalized twice. The first time was at 1 month of age with symptoms of splenomegaly, jaundice, and elevated liver enzymes, and the second time was at around age 2 for loss of mental and physical abilities. The patient presented with failure to thrive. According to paraclinical examinations, mildly delayed myelination along with a nonspecific periventricular hypersignal intensity was seen. Interestingly, the patient’s Niemann–Pick type C enzymatic function was evaluated twice and was negative on both occasions, while she was positive for NPC1 and NPC2 gene examinations. Conclusions In this study, despite the enzymatic study being negative, Niemann–Pick type C disease was finally confirmed, revealing the importance of mutations in Niemann–Pick type C pathogenesis. Besides, peripheral neuropathy was diagnosed in this patient as a very rare symptom of Niemann–Pick type C.

Introduction Elimination or blocking of astrocytes could ameliorate neuropathic pain in animal models. MiR-125a-5p, expressed in astrocyte derived extracellular vesicles, could mediate astrocyte function to regulate neuron communication. However, the role of miR-125a-5p in DPN (diabetic peripheral neuropathy) remains elusive. Materials and methods Type 2 diabetic mouse (db/db) was used as DPN model, which was confirmed by detection of body weight, blood glucose, mechanical allodynia, thermal hyperalgesia, glial fibrillary acidic protein (GFAP) and monocyte chemoattractant protein-1 (MCP-1). Astrocyte was isolated from db/db mouse and then subjected to high glucose treatment. The expression of miR-125a-5p in db/db mice and high glucose-induced astrocytes was examined by qRT-PCR analysis. Downstream target of miR-125a-5p was clarified by luciferase reporter assay. Tail vein injection of miR-125a-5p mimic into db/db mice was then performed to investigate role of miR-125a-5p on DPN. Results Type 2 diabetic mice showed higher body weight and blood glucose than normal db/m mice. Thermal hyperalgesia and mechanical allodynia were decreased in db/db mouse compared with db/m mouse, while GFAP and MCP-1 were increased in db/db mouse. High glucose treatment enhanced the protein expression of GFAP and MCP-1 in astrocytes. Sciatic nerve tissues in db/db mice and high glucose-induced astrocytes exhibited a decrease in miR-125a-5p. Systemic administration of miR-125a-5p mimic increased mechanical allodynia and thermal hyperalgesia, whereas it decreased GFAP and MCP-1. TRAF6 (tumor necrosis factor receptor associated factor 6) was validated as target of miR-125a-5p. Conclusion MiR-125a-5p in astrocytes attenuated DPN in db/db mice by up-regulation of TRAF6, which indicated the potential therapeutic effect.

Summary Ulnar nerve (UN) entrapment is a common peripheral neuropathy and can lead to dysfunction of both sensory and motor function of the hand. Surgical release is the mainstay of treatment, but post-operative rehabilitation of UN innervated intrinsic muscles is lacking evidence. This cohort study utilized surface electromyography (EMG) and assessed the activation of UN innervated intrinsic and extrinsic hand muscles during four exercises in healthy participants. Exercises included rotating baoding balls, squeezing a stress ball or grip device every second, and repetitive finger abduction against a rubber band. Normalized percent activation of each muscle was calculated for each exercise. It was demonstrated that rubber band resistance (RBR) finger abduction showed significantly increased activation in both intrinsic muscles tested, while minimizing activation of the one tested UN innervated extrinsic muscle. Thus, to best target the intrinsic hand muscles without fatiguing extrinsic muscles, the inexpensive and practical RBR exercise is beneficial in post-UN release rehabilitation.

Ahmed Esmat,1 Mahmoud I Elshamy,2 Doaa Mohamed Zakaria,3 Zakarya Shady,4 Eman Roshdy Mohamed,3 Nashwa El-Khouly,3 Marwa M Hassan,3 Fatma M El-Senosy3 1Department of Neurology, Al-Azhar University, Faculty of Medicine, Cairo, Egypt; 2Department of Radiology, Al-Azhar University, Faculty of Medicine, Cairo, Egypt; 3Department of Internal Medicine, Faculty of Medicine (Girls), Al-Azhar University, Cairo, Egypt; 4Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, EgyptCorrespondence: Zakarya Shady Tel +201001281304Email zakaryashady96@yahoo.comPurpose: Diabetes is a documented risk factor for peripheral neuropathy. It was reported that associated hypertension could increase this risk. The present study aimed to assess the effect of hypertension and diabetes on median nerve using high-resolution ultrasound.Methods: The study includes 50 hypertensive patients (HTN group), 50 diabetic patients (DM group), 50 patients with coexisting diabetes and hypertension (HTN + DM group) and 50 healthy controls. Median nerve affection in the studied groups was studied by vibration perception thresholds (VPT). The median nerve cross-sectional area was determined at the nerve cross-sectional area of the median nerve at the carpal tunnel by high-resolution ultrasound. Clinical symptoms were assessed using Toronto Clinical Severity Score (TCSS).Results: There was significantly higher median nerve CSA in all patient groups in comparison to controls. HTN + DM group had significantly higher median nerve CSA when compared with DM group. Patients with peripheral neuropathy in HTN + DM and DM groups had significantly higher median nerve CSA than patients without. Using ROC curve analysis, it was shown that median CSA could successfully distinguish patients with peripheral neuropathy from patients without in HTN + DM group [AUC (95% CI): 0.71 (0.54– 0.89)] and in DM group [AUC (95% CI): 0.86 (0.72– 0.99)].Conclusion: Hypertensive patients with and without diabetes have significantly higher median nerve CSA when compared with controls.Keywords: hypertension, peripheral neuropathy, high-resolution ultrasound, diabetes mellitus, median nerve

Background and Objectives: Gait and balance disturbances are challenging conditions in patients with Diabetic Peripheral Neuropathy (DPN). The overall literary consensus is that rehabilitation interventions are effective in improving gait performance in this patient group. This review sought to highlight and assess the literature and provide a scoping review on the current knowledge gaps in the rehabilitation interventions for the gait problems of patients with DPN. Methods: An electronic databases search was done between 2001 and May 2020. Besides, a hand-search method was used for grey literature. Two experts reviewed the results and screened them based on the subject’s diagnosis with DPN and gait problems. Results: Of 87 studies obtained, nine met the inclusion criteria. The frequent components of the rehabilitation interventions included exercise therapy, dual-task intervention, and the use of assistive devices. The outcomes utilized most frequently included changes in balance and stability, muscle strength, proprioception, function, and gait parameters. Conclusion: Evidence was formed as a scoping review to guide rehabilitation for DPN patients with gait problems. Rigorous comparative studies with clearly defined interventions are needed.

Although diabetic peripheral neuropathy is the most common diabetic microangiopathic complication, several other neuropathy syndromes can occur in the context of diabetes. We describe a rare case of polyneuropathy associated with diabetic ketoacidosis in a patient with new-onset type 1 diabetes. A 42-year-old man with diabetic ketoacidosis was admitted to our hospital with complications of respiratory and renal failure requiring mechanical ventilation and hemodialysis, respectively. After diabetic ketoacidosis improved from the critical state, he developed upper- and lower-limb paralysis with sensory disturbances and pain, as well as right facial paralysis, left recurrent nerve paralysis, and left hypoglossal nerve paralysis. Autonomic nervous function was also impaired. As the pathophysiology, prevention, and treatment of polyneuropathy associated with diabetic ketoacidosis are unclear, the neurologic function of diabetic ketoacidosis patients should be closely monitored.

Background. Paclitaxel-induced peripheral neuropathy (PIPN) is a major side effect of paclitaxel in patients with cancer with no fully known mechanisms. The aim of the study was to investigate the fine sub-microscopic structure of the spinal cord anterior horn neurons in PIPN combined with 2-ethyl-6-methyl-3-hydroxypyridine succinate administration. Methods. The experiment was performed on 80 white rats, which were administered intraperitoneally with Paclitaxel (Actavis, Romania), pre-dissolved in an isotonic saline at a dose of 2 mg / kg body weight four times a day to achieve a dose of 8 mg / kg. Then 48 of these animals were injected intraperitoneally 2-ethyl-6-methyl-3-hydroxypyridine succinate at a dose of 10 mg / kg (32 rats received intraperitoneally water for injection). Observation periods were 1, 7, 14, 21, 28 days. Results. We found that 2-ethyl-6-methyl-3-hydroxypyridine corrects the morpho-functional state of the motor neurons of the spinal cord and revealed a positive metabolic effect on them. Conclusion. This was manifested by the improvement of the electron microscopic picture of the neuronal structures responsible for their protein-synthetic (granular endoplasmic reticulum, ribosomes and polysomes), respiratory (mitochondria), and protective (lysosomes) functions.

Objective. The majority of women with primary Sjogren's syndrome (pSS) suffer from vaginal dryness, which negatively impacts daily and sexual activities. As little is known about the aetiology and clinical context of this complaint, this study investigated the relationship between vaginal dryness and other clinical parameters associated with pSS.Methods. Female participants of the REgistry of Sjogren syndrome at UMCG - LongiTudinal (RESULT) cohort who fulfilled ACR-EULAR and/or AECG classification criteria for pSS were included, using baseline data for analyses. Patient-reported vaginal dryness (range 0-10) was correlated with demographic characteristics, systemic disease activity (i.e. ESSDAI), Sjogren's Syndrome Disease Damage Index, salivary and lacrimal gland function, patient-reported outcomes (ESSPRI, MFI), serology and quality of life (SF-36, EQ-5D). Significantly associated parameters (pResults. This cross-sectional study included 199 women with pSS; mean age was 52 +/- 14 years, 53% were postmenopausal, and median vaginal dryness score was 5 (IQR 2-7). Vaginal dryness was significantly associated with older age, postmenopausal status, peripheral neuropathy, oral and ocular dryness, ESSPRI and SF-36 mental and general health. After correction for age, menopausal status and medication use, peripheral neuropathy (B=1.632), oral dryness (B=0.302), and ocular dryness (B=0.230) were independently associated with vaginal dryness.Conclusion. The independent association of vaginal dryness with oral and ocular dryness might imply that the aetiology of these symptoms is partly shared. Of all extraglandular features, only peripheral neuropathy was independently associated with vaginal dryness, suggesting that peripheral neuropathy plays a significant role in the pathology of vaginal dryness in pSS.

Objective. The majority of women with primary Sjogren's syndrome (pSS) suffer from vaginal dryness, which negatively impacts daily and sexual activities. As little is known about the aetiology and clinical context of this complaint, this study investigated the relationship between vaginal dryness and other clinical parameters associated with pSS. Methods. Female participants of the REgistry of Sjogren syndrome at UMCG - LongiTudinal (RESULT) cohort who fulfilled ACR-EULAR and/or AECG classification criteria for pSS were included, using baseline data for analyses. Patient-reported vaginal dryness (range 0-10) was correlated with demographic characteristics, systemic disease activity (i.e. ESSDAI), Sjogren's Syndrome Disease Damage Index, salivary and lacrimal gland function, patient-reported outcomes (ESSPRI, MFI), serology and quality of life (SF-36, EQ-5D). Significantly associated parameters (p Results. This cross-sectional study included 199 women with pSS; mean age was 52 +/- 14 years, 53% were postmenopausal, and median vaginal dryness score was 5 (IQR 2-7). Vaginal dryness was significantly associated with older age, postmenopausal status, peripheral neuropathy, oral and ocular dryness, ESSPRI and SF-36 mental and general health. After correction for age, menopausal status and medication use, peripheral neuropathy (B=1.632), oral dryness (B=0.302), and ocular dryness (B=0.230) were independently associated with vaginal dryness. Conclusion. The independent association of vaginal dryness with oral and ocular dryness might imply that the aetiology of these symptoms is partly shared. Of all extraglandular features, only peripheral neuropathy was independently associated with vaginal dryness, suggesting that peripheral neuropathy plays a significant role in the pathology of vaginal dryness in pSS.

The σ(2) receptor has attracted intense interest in cancer imaging(1), psychiatric disease(2), neuropathic pain(3–5), and other areas of biology(6,7). We determined the crystal structure of this receptor in complex with the clinical candidate roluperidone(2) and the tool compound PB28(8). These structures templated a large-scale docking screen of 490 million virtual molecules, of which 484 compounds were synthesized and tested. 127 new chemotypes with affinities superior to 1 μM were identified, 31 of which had affinities superior to 50 nM. Hit rate fell smoothly and monotonically with docking score. We optimized three hits for potency and selectivity, achieving affinities ranging from 3 to 48 nM with up to 250-fold selectivity versus the σ(1) receptor. Crystal structures of two new ligands bound to the σ(2) receptor confirmed the docked poses. To investigate the contribution of the σ(2) receptor in pain, two potent σ(2)-selective ligands and one potent σ(1)/σ(2) non-selective ligand were tested for efficacy in a mouse neuropathic pain model. All three ligands demonstrated time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model(9), supporting a role for the σ(2) receptor in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes to study under-explored areas of biology using structure-based screens of diverse, ultra-large libraries.

The enzyme ubiquitin-like modifier activating enzyme 5 (UBA5) plays an important role in activating ubiquitin-fold modifier 1 (UFM1) and its associated cascade. UFM1 is widely expressed and known to facilitate the post-translational modification of proteins. Variants in UBA5 and UFM1 are involved in neurodevelopmental disorders with early-onset epileptic encephalopathy as a frequently seen disease manifestation. Using whole exome sequencing, we detected a homozygous UBA5 variant (c.895C > T p. [Pro299Ser]) in a patient with severe global developmental delay and epilepsy, the latter from the age of 4 years. Magnetic resonance imaging showed hypomyelination with atrophy and T2 hyperintensity of the thalamus. Histology of the sural nerve showed axonal neuropathy with decreased myelin. Functional analyses confirmed the effect of the Pro299Ser variant on UBA5 protein function, showing 58% residual protein activity. Our findings indicate that the epilepsy currently associated with UBA5 variants may present later in life than previously thought, and that radiological signs include hypomyelination and thalamic involvement. The data also reinforce recently reported associations between UBA5 variants and peripheral neuropathy.