Signs Of Peripheral Neuropathy Research Articles

Long-term sensorimotor changes after a sciatic nerve block with bupivacaine and liposomal bupivacaine in a high-fat diet/low-dose streptozotocin rodent model of diabetes

IntroductionIt is unclear whether patients with diabetes are more susceptible to nerve toxicity of local anesthetics or whether nerve blocks can accelerate the progression of diabetic peripheral neuropathy. Bupivacaine is one of the most widely used local anesthetics for regional anesthesia despite many pre-clinical studies demonstrating neurotoxicity. Herein, we report the long-term functional consequences of sciatic nerve block with bupivacaine and liposomal bupivacaine (Exparel®) in an animal model of diabetes.MethodsMale Sprague Dawley rats were subject to standard chow/vehicle or high-fat diet/low-dose streptozotocin to induce a diabetic phenotype. Animals were then subdivided into groups that received repeated sciatic nerve blocks of saline, bupivacaine, or liposomal bupivacaine. Mechanical allodynia and thermal hyperalgesia were assessed prior to and 12 weeks following nerve blocks utilizing the von Frey and Hargreaves tests, respectively. Exploratory and locomotor activity were assessed with open field testing, and nerve conduction velocity testing was conducted prior to the termination of the study at 28 weeks.ResultsAnimals in the diabetic group developed sustained hyperglycemia >200 mg/dl and signs of peripheral neuropathy six weeks after treatment with streptozotocin, which persisted until the end of the study. Twelve weeks after a repeated sciatic nerve block with saline, bupivacaine, or liposomal bupivacaine, results indicate significant interaction effects of the disease group (control vs. diabetic) and local anesthetic treatment. Overall, diabetic status resulted in worse sensorimotor function compared to control animals. Treatment with perineural bupivacaine resulted in worse sensorimotor functions in both control and diabetic animals. Furthermore, bupivacaine treatment in diabetic animals with pre-existing neuropathy exacerbated sensorimotor function in some measures. In contrast, liposomal bupivacaine did not appear to cause any negative effects on functional outcomes for control or diabetic animals.ConclusionOur data indicate that bupivacaine, and not liposomal bupivacaine, causes long-term changes in tactile allodynia, thermal hyperalgesia, locomotor behaviors, and nerve conduction velocity in control as well as a high-fat diet/low-dose streptozotocin rodent model of diabetes. These results highlight the necessity to investigate safe peripheral nerve block strategies to preserve long-term functional independence in patients with or at risk for diabetic peripheral neuropathy.

WHEN AND WHERE DOES A CARRIER OF HEREDITARY TRANSTHYRETIN AMYLOIDOSIS (ILE88LEU) SHOW THE FIRST SIGNS OF THE DISEASE? DIAGNOSTIC CHALLENGES OF A NOT ONLY CARDIOGENIC MUTATION

Abstract We present the case of a 58–year–old man with a familiar history (mother affected) positive for ATTR–v (Ile88Leu) amyloidosis. The mother initially had a pure cardiac phenotype and was firstly treated with tafamidis, but progression of the disease to the nervous system warranted a switch to patisiran. Our patient carried the Ile88Leu mutation and had a medical history notable for surgically treated left carpal tunnel syndrome (CTS) and untreated right CTS. Furthermore, he was affected by systemic arterial hypertension and was a habitual smoker. He has been followed at our Institution since 2018. His first echocardiogram showed normal left ventricular ejection fraction (LVEF 65%), mild hypertrophy (anterior septum: 12 mm), and borderline values of GLS (– 16%) without any specific pattern. Further exams were executed: Bone scintigraphy (BS): negative (Perugini score 0); Coronary artery ct scan: moderate stenosis of proximal LAD; Neurologic evaluation: no signs of peripheral neuropathy. The clinical picture remained unaltered in 2020 and 2021. However, during November 2022 the patient developed atrial fibrillation (AF) and presented to the ED for dyspnea and palpitations. Electrical cardioversion was performed with success but subsequent recurrences warranted AF ablation in April 2023. At that moment, the patient was re–evaluated. Basal ECG did not show any significant alteration (FIg.1)This time, echocardiogram showed mild worsening of hypertrophy (13 mm septum), GLS – 16% with apical sparing pattern, no other major variations (Fig.2). BS was repeated and revealed grade 1 Perugini score (Fig.3). Hence, a series of clinical question arose: Should we begin a specific treatment or is the disease in an excessively early stage that does not warrant treatment? Is AF linked to concomitant arterial hypertension or might it be an early marker of disease? We questioned the usefulness of endomyocardial biopsy in this specific setting. In this case, we repeated electromyography that showed mild axonal sensitive–motor polyneuropathy. Finally, we concluded for initial signs of systemic amyloidosis ATTR–v (Ile88Leu) type with mixed phenotype (neurological+cardiac). The neurological involvement allowed us to start a gene–silencer (Patisiran). In conclusion, a periodic neurological evaluation is necessary and has crucial therapeutic implications in all genotypes. Indeed, there is increasing evidence that Ile88Leu is a not only cardiogenic mutation.

Omega-3 Fatty Acids Prevent Peripheral Neuropathy and Pro Inflammatory Adipose Tissue Macrophage Phenotype in High-Fat-Fed Mice

Obesity and/or consumption of a high fat diet is associated with the development of peripheral neuropathy (PN) which is characterized by changes in epidermal innervation and increased sensitivity in the extremities. Evidence indicates that omega-3 fatty acids prevent the development of PN and attenuate adipose inflammation, but the interaction of PN and adipose tissue macrophage (ATMΦ) phenotype have not been investigated. We hypothesized that a diet high in unsaturated fatty acids may prevent PN and adipose inflammation, despite the high fat content. PURPOSE: Assess the effects of omega-3 fatty acids on signs of PN and ATMΦ phenotype in high-fat-fed mice. Methods: Male C57Bl/6 mice were randomized to (n = 12-14/group): 10% low fat fish oil (10% FO); 54% high fat fish oil (54% FO); 10% low fat lard (10% L); or 54% high fat lard (54% L) for 14 weeks. PN was characterized by the von Frey test for hindpaw sensitivity at baseline then biweekly through week 14. After 14 weeks, intraepidermal nerve fiber density (IENFD) was quantified by immunohistochemistry of the hindpaw footpad skin using anti-PGP 9.5. The relative percentage of total macrophage cells (F4/80+CD11b+) and M1 (CD206-CD11c+) and M2 (CD206+CD11c-) cell populations in epididymal adipose were identified using flow cytometry. Group differences were identified by 2 x 2 factorial ANOVA. Pearson correlations were used to assess the relationship between hindpaw withdrawal threshold and ATMΦ. Results: 54% L (35.3 ± 1.0 g) had greater body mass compared to all other groups: 10% FO (26.5 ± 0.7, p < 0.001); 10% L (27.8 ± 0.6, p = 0.001); and 54% L (35.3 ± 1.0, p < 0.001). Similarly, fasting insulin was greater in 54% L (3.1 ± 0.4 ng/mL) compared to all other groups: 10% FO (1.0 ± 1.0, p < 0.001); 10% L (1.6 ± 0.2, p < 0.001), and 54% FO (1.0 ± 0.1, p < 0.001). Fasting glucose was greater in 54% L (225.8 ± 7.5 mg/dl) compared to 10% FO (216.1 ± 7.7, p =0.04) and 54% FO (182.6 ± 6.6, p = 0.03), but not 10% L (180.7 ± 17.1, p = 0.483). Following the same pattern as body mass and insulin, homeostatic model assessment of insulin resistance (HOMA-IR) was greater in 54% L (8.1 ± 1.1) compared to all other groups: 10% FO (2.2 ± 0.4, p < 0.001); 10% L (4.1 ± 0.6, p < 0.001); and 54% FO (2.2 ± 0.3, p < 0.001). Hindpaw sensitivity was greater in 54% L (0.08 ± 0.02 g) compared to 54% FO (0.19 ± 0.03, p = 0.02). IENFD was greater in 54% L (52.5 ± 2.2 fibers per mm) compared to 10% FO (44.1 ± 1.5, p = 0.04), but was not different from 10% L (49.7 ± 2.8, p = 0.47) or 54% FO (48.1 ± 3.0, p = 0.24). M1 ATMΦ percentage was greater in 54% L (11.7 ± 2.5 %) compared to all other groups: 10% L (3.8 ± 0.8, p = 0.001), 10% FO (5.2 ± 0.7, p = 0.014), and 54% FO (5.1 ± 0.6 %, p = 0.016). M2 ATMΦ percentage was greater in 10% L (59.7 ± 4.5 %) compared to all other groups: 10% FO (42.1 ± 5.0, p = 0.036), 54% L (41.4 ± 3.9, p = 0.027), and 54% FO (31.4 ± 3.6 %, p < 0.001), but there were no significant differences in M2 ATMΦ percentage in 54% L vs. 54% FO. There were no significant correlations between hindpaw sensitivity and M1 ATMΦ percentage, M2 ATMΦ percentage, or M1:M2 ratio. CONCLUSION: The negative metabolic effects of a high fat lard diet on body mass, glucose, insulin, and insulin resistance were prevented when the dietary fat source was omega-3 fatty acids instead of lard. Notably, mice fed a high fat lard diet had a higher percentage of the pro inflammatory M1 ATMΦ phenotype and developed signs of painful PN including hindpaw hypersensitivity and increased IENFD but these effects were prevented by omega-3 fatty acids in the 54% FO group, despite the high dietary fat content. Supported by the Southern Illinois University Edwardsville Vaughnie Lindsay New Investigator Award. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Polatuzumab vedotin pharmacokinetics in a hemodialysis patient with diffuse large B-cell lymphoma.

Chemotherapy for the hemodialysis (HD) patient is a challenging situation because it requires special considerations including dose modifications and timing of drug administration in relation with HD sessions. Polaltuzumab vedotin (PV), an antibody-drug conjugate in which monomethyl auristatin E (MMAE) is linked to an anti-CD79b monoclonal antibody, is an extremely promising therapeutic for treating diffuse large B cell lymphoma (DLBCL), but the pharmacokinetics are unknown in HD patients. We carried out pharmacokinetic studies of PV when administered at 1.2mg/kg to a DLBCL patient on HD, and compared the results with that of non-HD patients. PV was administered in conjunction with bendamustine and rituximab. Serum concentration-time curves of both antibodyconjugated and unconjugated MMAE in the presented HD patient were similar compared to that of non-HD patients. We also demonstrate that elimination of both antibody-conjugated and unconjugated MMAE through HD is limited. PV administration at 1.2mg/kg to an HD patient was also clinically feasible, and no signs of peripheral neuropathy were observed. PV therapy may be a relatively safe treatment method for DLBCL patients on HD.

Abstract 2702: GQ1001 is a next generation HER2-targeting ADC with excellent druggability, safety and potency

Abstract Background: GQ1001 was developed to overcome the current limitation of existing HER2 ADCs by using the next generation site-specific conjugation and a stable linker technology, coined the intelligent ligase-dependent conjugation (iLDC) technology. iLDC provides a robust platform for the generation of ADC with high homogeneity and excellent stability. Our data show that GQ1001 is highly homogeneous with strong anti-tumor potency, more importantly, markedly enhanced linker stability and reduced off-target toxicity, and points to a safer HER2 ADC with a larger therapeutic window in human. Methods: In vitro and in vivo anticancer efficacy and the mechanism of action (MOA) of GQ1001 were assessed using several HER2+ cancer cell lines and animal models. Ex vivo linker stability was assessed by incubating GQ1001 with the plasma from different species. Pharmacokinetics in cynomolgus monkeys and safety profiles in rats and monkeys were evaluated. Results: GQ1001 was generated by conjugating trastuzumab to DM1 via an unique open-ring containing linker and the enzyme-based site-specific conjugation technology that significantly increases the stability of GQ1001. Optimal physiochemical property of GQ1001was demonstrated from the long-term stability study in liquid formulation. GQ1001 demonstrated similar in vitro anti-cancer activities to T-DM1 in HER2+ tumor cells. However, T-DM1 showed significant non-specific cytotoxicity in HER2- cells while GQ1001 didn’t. In animal studies, GQ1001 induced a robust dose-dependent tumor growth inhibition in multiple HER2-positive CDX and PDX models. From the combo treatment studies, GQ1001 showed synergistic anti-tumor response when combined with HER2-targeting tyrosine kinase inhibitors TKIs and chemotherapeutic agents in multiple HER2-positive models, including those resistant to anti-HER2 TKIs and/or mAbs. In ex vivo plasma stability assay, the DM1-shedding ratio of GQ1001 in human plasma was ~1/100th of that of T-DM1. This supreme linker stability was confirmed by the favorable pharmacokinetics in monkey with extremely low free DM1 exposure in circulation at a significantly lower level than T-DM1. The highest non-severely toxic dose HNSTD of GQ1001 in monkey was 45 mg/kg without any signs of peripheral neuropathy and interstitial lung disease, suggesting GQ1001 will demonstrate excellent tolerance in human. Consistent with this preclinical data, GQ1001 demonstrated superior tolerability profile in heavily pretreated HER2-positive advanced solid tumors patients in a global, open labeled multicenter phase Ia trial. Conclusions: GQ1001 is a unique HER2-targeting ADC that exhibits markedly-enhanced linker stability and safety profiles. Judging from preclinical data, GQ1001 demonstrates the potential to treat HER2-positive cancer patients, alone or in combination, who have progressed on previous HER2-targeting therapeutics with reduced toxicity. Citation Format: Lei Huang, Lili Shi, Yajun Sun, Cao Lv, Chengcheng Gong, Chong Liu, Jun Yang, Lu Jiang, Jinduo Yuan, Xuesong Li, Mingyu Hu, Xinju Gao, Yu Si, Hui Yang, Yan Shi, Bo Yang, Paul H. Song, Gang Qin, Biyun Wang. GQ1001 is a next generation HER2-targeting ADC with excellent druggability, safety and potency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2702.

The PanGut-study: Evoked potentials following rectal balloon distention, a way of evaluating diabetic autonomic neuropathy in the gut?

AimThere is a lack of methods for investigating the autonomic nerves of the gastrointestinal tract. Our aim was to explore a novel test measuring visceral sensory evoked potentials (EPs) in response to rapid balloon distention in the rectum and compare it to established tests for diabetic neuropathy. MethodParticipants with longstanding type 2 diabetes, newly onset, untreated diabetes <1 year, and matched controls, were included. Tests included cardiovascular reflex tests, orthostatic blood pressure, electrical skin conductance assessment, sural nerve testing and monofilament test. The rectal balloon distention pressure at earliest sensation and threshold of unpleasantness were identified and used to elicit mechanical EPs. ResultsThe pressure at earliest sensation was higher in people with diabetes, 0.038 (0.012) bar vs. controls 0.030 (0.009) bar, p = 0.002, and in people with signs of peripheral neuropathy, 0.045 (0.014) bar, p < 0.01. Clinical correlations between EP amplitude and latency, and other tests were found. ConclusionsRectal hyposensitivity was associated with both longstanding and early diabetes, indicating enteric sensory dysfunction already in early stages of diabetes. Correlation analyses may indicate that central afferent processing is affected in parallel with peripheral neuronal function.

Th1/Th17-mediated Immunity and Protection from Peripheral Neuropathy in Wildtype and IL10-/- BALB/c Mice Infected with a Guillain-Barré Syndrome-associated Campylobacter jejuni Strain.

Campylobacter jejuni is an important cause of bacterial gastroenteritis worldwide and is linked to Guillain-Barré syndrome (GBS), a debilitating postinfectious polyneuropathy. The immunopathogenesis of GBS involves the generation of antibodies that are cross reactive to C. jejuni lipooligosaccharide and structurally similar peripheral nerve gangliosides. Both the C. jejuni infecting strain and host factors contribute to GBS development. GBS pathogenesis is associated with Th2-mediated responses in patients. Moreover, induction of IgG1 antiganglioside antibodies in association with colonic Th2-mediated immune responses has been reported in C. jejuni-infected C57BL/6 IL10-/- mice at 4 to 6 wk after infection. We hypothesized that, due to their Th2 immunologic bias, BALB/c mice would develop autoantibodies and signs of peripheral neuropathy after infection with a GBS patient-derived strain of C. jejuni (strain 260.94). WT and IL10-/- BALB/c mice were orally inoculated with C. jejuni 260.94, phenotyped weekly for neurologic deficits, and euthanized after 5 wk. Immune responses were assessed as C. jejuni-specific and antiganglioside antibodies in plasma and cytokine production and histologic lesions in the proximal colon. Peripheral nerve lesions were assessed in dorsal root ganglia and their afferent nerve fibers by scoring immunohistochemically labeled macrophages through morphometry. C. jejuni 260.94 stably colonized both WT and IL10-/- mice and induced systemic Th1/Th17-mediated immune responses with significant increases in C. jejuni-specific IgG2a, IgG2b, and IgG3 plasma antibodies. However, C. jejuni 260.94 did not induce IgG1 antiganglioside antibodies, colitis, or neurologic deficits or peripheral nerve lesions in WT or IL10-/- mice. Both WT and IL10-/- BALB/c mice showed relative protection from development of Th2-mediated immunity and antiganglioside antibodies as compared with C57BL/6 IL10-/- mice. Therefore, BALB/c mice infected with C. jejuni 260.94 are not an effective disease model but provide the opportunity to study the role of immune mechanisms and host genetic background in the susceptibility to post infectious GBS.

Clinical Characteristics of Peripheral Neuropathy in Kenyan Patients with HIV Infection Compared with Patients with Concurrent HIV Infection and Diabetes Mellitus.

IntroductionPersons living with human immunodeficiency virus (HIV) are living longer and at risk of non-communicable diseases, including diabetes mellitus (DM). Both HIV and DM place patients at risk of peripheral neuropathy (PN). Our aim was to demonstrate the prevalence and characteristics of PN in our population of patients with HIV infection compared with concomitant HIV and DM.MethodsA prospective cross-sectional study was performed at the Aga Khan Hospital in Nairobi, Kenya. Data were collected on demographics and characteristics of DM and HIV. Symptoms and signs of PN were evaluated by Neuropathy Symptom Score, Neuropathy Disability Score, and 10 g monofilament testing.ResultsTwo groups were recruited, each consisting of 68 patients: (1) HIV only, (2) HIV and DM. The median age of patients was 51 years (IQR 42.8–58.6) and 55% were male. Median duration for HIV was 10 years (IQR 5–12) with a median CD4 count of 524 cells/mm3 (IQR 369–731). Median duration for DM was 1 year with a median glycosylated hemoglobin of 6.7% (IQR 6.6–7.6). Sixty-nine percent of patients with HIV had suppressed viral loads, and 9 patients (6.6%) had a history neurotoxic antiretroviral therapy use. PN was detected in 11 (16%) HIV-only patients, and in 17 (25%) participants who had both HIV and DM (Fisher exact test chi-square = 0.4). Univariate analysis demonstrated older age, high body mass index, and long duration of HIV were associated with an OR of 1.07 (95% CI 1.02–1.11), 1.21 (95% CI 0.46–3.11), and 1.07 (95% CI 0.99–1.15) in the overall group, respectively.ConclusionOur study demonstrates a higher but non-significant prevalence of PN in patients with both HIV and DM when compared to HIV alone. HIV disease control had no association with PN presence.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01205-3.

Alarming increase in poisonings from recreational nitrous oxide use after a change in EU-legislation, inquiries to the Dutch Poisons Information Center.

After the change in EU-legislation in 2014, recreational use of nitrous oxide (N2O) increased in the Netherlands from 2015 onwards. We studied the effect on N2O poisonings during an 11 year period. A retrospective observational study was performed on the incidence rate of N2O poisonings, relative to all recreational drug poisonings reported to the Dutch Poisons Information Center (DPIC) from 2010-2020. Secondary outcomes were the frequency of heavy use, frequent use, co-exposures, and toxicity in 2019 and 2020. 433 N2O poisonings were included. The incidence rate increased exponentially from 0.12% in 2010 to 11% in 2020, with an average monthly rate of 3.8%. In 2019 and 2020, 79% of the patients indicated heavy use, frequent use or both, and 42% used from large cylinders. Chronic toxicity (signs of peripheral neuropathy) was reported in 38% of the patients. The rate of N2O poisonings increased alarmingly in the Netherlands. An increasing proportion of patients reported problematic heavy or frequent use, accompanied by chronic toxicity.

Периферійна нейропатія при хламідійному реактивному артриті

Актуальність: периферійна нейропатія (ПНП) при реактивному хламідійному урогенітальному артриті (РХА) описується у вигляді поодиноких спостережень, і багато клініко-патогенетичних аспектів такого ураження нервової системи залишаються нез’ясованими. Мета дослідження: оцінити частоту й характер перебігу ПНП при РХА, взаємозв’язок нервових та суглобових ушкоджень, вивчити питання патогенетичних побудов цієї нейропатії, виділити чинники ризику. Матеріал і методи. Під наглядом перебував 101 хворий на РХА, середній вік яких становив 32 роки, тривалість захворювання — 4 роки, а співвідношення чоловіків і жінок — 1 : 1. У 90 % спостережень РХА виявлено Chlamydia trochamatis у секреті передміхурової залози, зіскобах з уретри, шийки матки, стінок піхви, у 83 % — позитивні серологічні тести на хламідійну інфекцію. Результати. При РХА ознаки ПНП мають місце в 19 % хворих у співвідношенні мононейропатія/полінейропатія як 1 : 1, із моторними, сенсорними і змішаними розладами в пропорції 1 : 3 : 6, наявністю вегетативних змін у кожного другого пацієнта та частішою дистальною локалізацією процесу в руках, на що впливають тяжкість перебігу суглобового синдрому, високі рівні протихламідійних антитіл у крові, а на аксональні й демієлінізуючі показники електронейроміографії — вираженість уражень урогеніталій і наявність синдрому Гійена — Барре. Високий показник темпів прогресування артриту є прогнознегативною ознакою перебігу ПНП у хворих на РХА. У патогенетичних побудовах ПНП беруть участь запальні імунні білки, порушення ендотеліальної функції судин та фізико-хімічні поверхневі реологічні властивості сироватки. Висновок. ПНП має місце в кожного п’ятого пацієнта з РХА, взаємопов’язана з клініко-лабораторними ознаками уражень суглобів, а в майбутньому буде корисним активне виявлення такої патології нервової системи для подальших своєчасних реабілітаційних заходів, причому серопозитивність РХА за антитілами до циклічного цитрулінового пептиду є чинником ризику такої ПНП.

Laser doppler flowmetry as the advanced non-invasive method of evaluation оf microcirculation status in patients with diabetes mellitus

Currently, the problem of diabetes mellitus (DM) is one of the most important medical and social challenges worldwide. This is primarily due to the widespread prevalence of the disease and tendency to further increase in the incidence of diabetes mellitus.Systemic microcirculatory disorders play an impor­tant role in the pathogenesis of DM complications. They lead to the development of microangiopathy and neuropathy through the primary lesion of vessels involved in the blood supply of the peripheral parts of the nervous system. Currently, less than one-third of physicians recognize signs of peripheral neuropathy associated with diabetes. Untimely diagnosis contributes significantly to high morbidity, disability, and mortality.The authorinvestigates the experience of the use of laser Doppler flowmetry (LDF) in clinical practice as a method of studying the state of the microcirculatory bed in patients with diabetes mellitus.LDF is a non-invasive quantitative method of microcirculation assessment; its capabilities include the analysis of microcirculatory rhythms and functional testing with different types of provocative effects, which provides with investigating the state of regulatory mechanisms of microcirculation. The prevention and treatment of various microcirculatory disorders is one of the most important problems of medical practice. The difficulties of studying the microcirculation are caused by the very small size of microvessels and strong ramification of intra-organic vascular networks. The use of LDF in scientific research will make it possible toreveal the DM-specific changes in microcir­culatory bed functioning. The findings of some studies suggest that microcirculatory disorders are not only a pathogenetic link in the development of complications, but they are also observed in patients with early disorders of carbohydrate metabolism and may precede the manifestation of diabetes. However, the method has not yet become widespread in clinical practice.

Systemic inflammatory biomarkers in painful diabetic neuropathy.

We conducted a systematic review of the literature with meta-analysis to determine whether painful diabetic neuropathy is associated with a specific inflammatory profile. The study is based on the PRISMA statement for systematic reviews. We performed a search of published studies up until January 2021 in MEDLINE and Web of Science based on heading and free text terms. The search strategy included the phrases: diabetic peripheral neuropathy, painful peripheral neuropathy individually and in combination with the terms: inflammation and inflammatory biomarkers. We screened titles and abstracts and performed data extraction. We also manually searched the article titles in the reference lists of key studies and reviews published in the last 20years. Data extracted from the studies included study design, inclusion and exclusion criteria, sample type including serum and plasma, source of the sample including patients with peripheral diabetic neuropathy or patients with painful and painless neuropathy of any etiology. Blood concentrations of all measured cytokines were recorded. Whenever possible we calculated the effect size and confidence interval. Non-human studies were excluded from the meta-analysis. Thirteen studies were included in this meta-analysis. The study design was cross-sectional, case control or cohort type studies. Specific inflammatory mediators are significantly higher in painful than in painless diabetic neuropathy as well as in painful neuropathies of any etiology. Markers of inflammation are also increased in those patients with diabetes mellitus, who suffer from peripheral neuropathy in comparison to patients with diabetes mellitus but no signs of peripheral neuropathy. A proinflammatory state may be the common denominator of pain and peripheral neuropathy in patients with diabetes mellitus but the inflammatory profiles seem to differ.

Electrophysiological estimation of subclinical neuropathy and its types in diabetes mellitus patients

Diabetes mellitus is the leading cause for peripheral neuropathy in India. It is a devastating complication which leads to amputation of limbs affecting the physical and social quality of life. Subclinical peripheral neuropathy is one which doesn’t have any symptoms or signs, but positive electrophysiological findings.: 1): To estimate the prevalence of subclinical peripheral neuropathy and its types among the diabetes mellitus patients. 2): To determine the various risk factors influencing them. 51 patients with diabetes mellitus without symptoms and signs of peripheral neuropathy were selected based on inclusion criteria and after assessing the screening scores. Necessary blood investigations was done and nerve conduction test was carried out in both upper and lower limbs for motor and sensory study.22(43%) out of the 51 diabetic patients had subclinical peripheral neuropathy. Lower limb(29.5%) predmominates than upper limb, sensory(23.5%) more common than motor neuropathy. Axonal neuropathy was the predominant (29%). Statistical significance was observed between the duration of diabetes mellitus, high triglyceride levels, high blood sugar profile and high HbA1C values with the presence of subclinical peripheral neuropathy.Nerve conduction study is the best for diagnosing subclinical neuropathy in diabetes mellitus patients. By early diagnosis and control of diabetes we can prevent dreadful complications.

A case of intraneural ganglion cyst of the peroneal nerve: A rapid recovery after incision of cyst

Introduction : Intraneural ganglion cysts (INGCs) are an infrequent cause of foot drop. INGCs are benign mucinous cysts within the epineurium of peripheral nerves, which are usually observed in the peroneal nerve at the knee typically leading to symptoms and signs of peripheral neuropathy. Case Report: A 40-year-old man with foot drop who had undergone a spinal study for discopathy was examined in this study. The patient had peroneal nerve compression at the neck of the fibula resulting from an extra neural cyst. Surgical exploration revealed an intraneural cyst. Epineurium was incised and the cyst was evacuated. In a two-week post-surgery follow up, his foot drop had improved partially and the remainder of his symptoms resolved. Conclusion: Awareness of the intraneural cysts of peroneal nerve as a cause for foot drop is important because early surgical intervention could reverse the course of disease.

The effects of a physiotherapist-led exercise intervention on peripheral neuropathy among people living with HIV on antiretroviral therapy in Kigali, Rwanda.

BackgroundHIV-associated peripheral neuropathy (PN) is common in people living with HIV. Its management is mostly symptomatic utilising pharmacological approaches.ObjectivesThis study determined the effects of an exercise intervention on PN among Rwandan people living with HIV receiving antiretroviral therapy (ART).MethodsA 12-week single-blinded randomised controlled trial using the Brief Peripheral Neuropathy Screen (BPNS) as the assessment tool tested the effects of an exercise intervention on PN, followed by a 12-week non-intervention period. A total of 120 people with HIV- associated PN on ART were randomised to an exercise or no exercise group. Both groups continued receiving routine care. A bivariate analysis using Pearson’s chi-square test for significant differences in PN symptoms and signs, between groups, at baseline, after the 12 weeks intervention and 12 weeks post-intervention using generalised linear regression models to determine predictors of treatment outcomes was undertaken, utilising an intention-to-treat analysis (alpha p ≤ 0.05).ResultsAt 12 weeks, the intervention group compared to the control: neuropathic pain 70% versus 94% (p < 0.005), PN symptoms severity – mild and/or none in 85% versus 60% (p < 0.001) and radiation of PN symptoms reduced, 80% versus 37% (p < 0.001). There were no differences in PN signs at 12 weeks intervention and at 12 weeks post-intervention. Having changed the antiretroviral (ARV) and having developed PN symptoms after the start on ARVs predicted treatment improvement, while demographic factors did not predict any treatment outcome.ConclusionA physiotherapist-led exercise intervention improved PN symptoms, but with non-significant improvement in PN signs. Factors related to early diagnosis and treatment of PN were facilitators for the improvement of PN symptoms.Clinical implicationsPhysiotherapist-led exercises should be integrated into the routine management of people living with HIV on ART with PN symptoms.

Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs.

Clinical, pathological, and genetic findings of a primary hereditary ataxia found in a Malinois dog family are described and compared with its human counterpart. Based on the family history and the phenotype/genotype relationships already described in humans and dogs, a causal variant was expected to be found in KCNJ10. Rather surprisingly, whole-exome sequencing identified the SLC12A6 NC_006612.3(XM_014109414.2): c.178_181delinsCATCTCACTCAT (p.(Met60Hisfs*14)) truncating variant. This loss-of-function variant perfectly segregated within the affected Malinois family in an autosomal recessive way and was not found in 562 additional reference dogs from 18 different breeds, including Malinois. In humans, SLC12A6 variants cause "agenesis of the corpus callosum with peripheral neuropathy" (ACCPN, alias Andermann syndrome), owing to a dysfunction of this K+-Cl- cotransporter. However, depending on the variant (including truncating variants), different clinical features are observed within ACCPN. The variant in dogs encodes the shortest isoform described so far and its resultant phenotype is quite different from humans, as no signs of peripheral neuropathy, agenesis of the corpus callosum nor obvious mental retardation have been observed in dogs. On the other hand, progressive spinocerebellar ataxia, which is the most important feature of the canine phenotype, hindlimb paresis, and myokymia-like muscle contractions have not been described in humans with ACCPN so far. As this is the first report of a naturally occurring disease-causing SLC12A6 variant in a non-human species, the canine model will be highly valuable to better understand the complex molecular pathophysiology of SLC12A6-related neurological disorders and to evaluate novel treatment strategies.

Non-invasive Focal Mechanical Vibrations Delivered by Wearable Devices: An Open-Label Pilot Study in Childhood Ataxia

Non-invasive focal mechanical vibrations (NIFMV) now represent a strategy of increasing interest to improve motor control in different neurological diseases. Nanotechnology allowed the creation of wearable devices transforming thermal variations into mechanical energy with focal vibrations. This kind of wearable stimulators (WS) has produced encouraging preliminary results when used in the treatment of movement disorders and ataxia in adults. In this open label pilot study we first evaluated the feasibility, safety and effectiveness of NIFMV by WS in a cohort of 10 patients with childhood ataxia, a phenomenological category including different conditions still lacking of effective symptomatic therapies. Through the assessment of both clinical rating scales and spatio-temporal gait parameters via standardized gait analysis, we observed that a 4 weeks long treatment with WS Equistasi® was safe and provided significantly different effects in stride features of patients with slow/non-progressive cerebellar ataxia and Friedreich's Ataxia. Although limited by the sample size, the absence of a placebo-controlled group, the poor compliance of enrolled population to the original experimental design and the partial accuracy of outcome measures in pediatric subjects, we suggest that NIFMV by WS could support locomotion of patients with childhood slow/non-progressive cerebellar ataxia with preserved sensory system and no signs of peripheral neuropathy. Future studies are definitely necessary to confirm these preliminary results and define criteria for successful NIFMV-based treatment

Impaired vibrotactile sense in children and adolescents with type 1 diabetes - Signs of peripheral neuropathy.

ObjectiveTo investigate whether multi-frequency vibrometry can identify individuals with elevated vibration perception thresholds (VPTs), reflecting impaired vibrotactile sense, among children and adolescents with type 1 diabetes.MethodsIn 72 pediatric patients with type 1 diabetes, VPTs were evaluated for seven frequencies on two sites of the hand, and five frequencies on two sites of the foot. Z-scores, based on previously collected reference data, were calculated. Perception to light touch was investigated using monofilaments. Subjects’ characteristics were analyzed in comparison to normal and impaired vibrotactile sense.ResultsSubjects’ median age, disease duration and age at disease onset were 12.8, 5.3 and 6.9 years, respectively. A total of 13 out of 72 (18%) subjects had impaired vibrotactile sense on at least one foot site. Impaired vibrotactile sense was more common among subjects treated with multiple daily insulin injections (MDI) compared to subjects treated with continuous subcutaneous insulin infusion (CSII) (p = 0.013). Age at disease onset was higher among subjects with impaired vibrotactile sense (p = 0.046). No significant correlations were found with gender, HbA1c or duration of diabetes.ConclusionsImpaired vibrotactile sense, mirroring diabetic peripheral neuropathy, was found in 1/5 of the children and adolescents in the study, and was more common in patients treated with MDI than in subjects treated with CSII.

Pepsin Egg White Hydrolysate Improves Glucose Metabolism Complications Related to Metabolic Syndrome in Zucker Fatty Rats.

The purpose of this study was to evaluate the effect of the administration of two egg white hydrolysates on glucose metabolism complications related to Metabolic Syndrome (MS) in Zucker fatty rats (ZFR). ZFR were given 750 mg/kg/day of egg white hydrolyzed with pepsin (HEW1) or with aminopeptidase (HEW2) for 12 weeks in their drinking water or just water. Zucker lean rats (ZLR), which received water, were used as a control. The presence of tactile allodynia, which is a sign of peripheral neuropathy, was assessed. Blood samples and pancreas were collected to determine the effect of the hydrolysates on glucose metabolism. The intake of HEW1 significantly lowered plasma insulin levels and improved the quantitative indexes of insulin resistance, insulin sensitivity, and pancreatic β-cell functionality (HOMA-IR, HOMA-β, and QUICKI, respectively), but non-significant changes were observed in group treated with HEW2. Compared to ZLR, ZFR showed tactile allodynia, but the consumption of both hydrolysates significantly increased mechanical sensitivity in ZFR. In conclusion, HEW1 pepsin could improve the glucose metabolism abnormalities associated with MS in obese Zucker rats.

High resolution ultrasonography of the tibial nerve in diabetic peripheral neuropathy.

Aim of the studyHigh-resolution ultrasonography of the tibial nerve is a fast and non invasive tool for diagnosis of diabetic peripheral neuropathy. Our study was aimed at finding out the correlation of the cross sectional area and maximum thickness of nerve fascicles of the tibial nerve with the presence and severity of diabetic peripheral neuropathy.Material and methods75 patients with type 2 diabetes mellitus clinically diagnosed with diabetic peripheral neuropathy were analysed, and the severity of neuropathy was determined using the Toronto Clinical Neuropathy Score. 58 diabetic patients with no clinical suspicion of diabetic peripheral neuropathy and 75 healthy non-diabetic subjects were taken as controls. The cross sectional area and maximum thickness of nerve fascicles of the tibial nerves were calculated 3 cm cranial to the medial malleolus in both lower limbs.ResultsThe mean cross sectional area (22.63 +/− 2.66 mm2) and maximum thickness of nerve fascicles (0.70 mm) of the tibial nerves in patients with diabetic peripheral neuropathy compared with both control groups was significantly larger, and statistically significant correlation was found with the Toronto Clinical Neuropathy Score (p < 0.001). The diabetic patients with no signs of peripheral neuropathy had a larger mean cross sectional area (14.40 +/− 1.72 mm2) and maximum thickness of nerve fascicles of the tibial nerve (0.40 mm) than healthy non-diabetic subjects (12.42 +/− 1.01 mm2 and 0.30 mm respectively).ConclusionThe cross sectional area and maximum thickness of nerve fascicles of the tibial nerve is larger in diabetic patients with or without peripheral neuropathy than in healthy control subjects, and ultrasonography can be used as a good screening tool in these patients.