Prevalence and clinical characteristics of diabetic peripheral neuropathy in hospital patients with Type 2 diabetes in Korea

Diabet. Med. 29, e290-e296 (2012) ABSTRACT: Aims Diabetic peripheral neuropathy is a common complication of diabetes. This cross-sectional study investigated the prevalence and clinical characteristics of this neuropathy in patients with Type?2 diabetic mellitus treated at hospitals in Korea. Methods Questionnaires and medical records were used to collect data on 4000 patients with Type?2 diabetes from the diabetes clinics of 40 hospitals throughout Korea. Diabetic peripheral neuropathy was diagnosed based on a review of medical records or using the Michigan Neuropathy Screening Instrument score and monofilament test. Results The prevalence of neuropathy was 33.5% (n?=?1338). Multivariate analysis revealed that age, female sex, diabetes duration, lower glycated haemoglobin, treatment with oral hypoglycaemic agents or insulin, presence of retinopathy, history of cerebrovascular or peripheral arterial disease, presence of hypertension or dyslipidaemia, and history of foot ulcer were independently associated with diabetic peripheral neuropathy. Of the patients with neuropathy, 69.8% were treated for the condition and only 12.6% were aware of their neuropathy. Conclusion There was a high prevalence of peripheral neuropathy in patients with Type?2 diabetes in Korea and those patients were far more likely to have complications or co-morbidities. The proper management of diabetic peripheral neuropathy deserves attention from clinicians to ensure better management of diabetes in Korea.     

Decreased response of epinephrine and norepinephrine to insulin-induced hypoglycemia in diabetic autonomic neuropathy

The responses of epinephrine, norepinephrine and other counter-regulatory hormones to insulin-induced hypoglycemia were investigated in 5 diabetics who showed signs of autonomic neuropathy, in 7 age-matched diabetics without autonomic neuropathy and in 7 healthy subjects. The presence of autonomic neuropathy was evaluated by decreased beat-to-beat variation in heat rates during hyperventilation or orthostatic hypotension. Catecholamines were determined by a totally automated plasma catecholamine analyzing system using a two-column system of high performance liquid chromatography. Plasma epinephrine and norepinephrine responses to hypoglycemia in diabetics with autonomic neuropathy were significantly lower than those in diabetics without autonomic neuropathy. Plasma glucagon response in diabetics was apparently attenuated compared to normal controls and there was no significant difference in glucagon response between the two patient groups. Other counter-regulatory hormone responses did not differ among the three groups. The data demonstrate that the responses of plasma epinephrine and norepinephrine to insulin-induced hypoglycemia are impaired in diabetics with autonomic neuropathy.     

Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation: no causal relation with diabetic autonomic neuropathy.

OBJECTIVE--To examine the traditional view that unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation in insulin dependent diabetes mellitus are manifestations of autonomic neuropathy. DESIGN--Perspective assessment of unawareness of hypoglycaemia and detailed assessment of autonomic neuropathy in patients with insulin dependent diabetes according to the adequacy of their hypoglycaemic counterregulation. SETTING--One routine diabetic unit in a university teaching hospital. PATIENTS--23 Patients aged 21-52 with insulin dependent diabetes mellitus (seven with symptoms suggesting autonomic neuropathy, nine with a serious clinical problem with hypoglycaemia, and seven without symptoms of autonomic neuropathy and without problems with hypoglycaemia) and 10 controls with a similar age distribution, without a personal or family history of diabetes. MAIN OUTCOME MEASURES--Presence of autonomic neuropathy as assessed with a test of the longest sympathetic fibres (acetylcholine sweatspot test), a pupil test, and a battery of seven cardiovascular autonomic function tests; adequacy of hypoglycaemic glucose counterregulation during a 40 mU/kg/h insulin infusion test; history of unawareness of hypoglycaemia; and response of plasma pancreatic polypeptide during hypoglycaemia, which depends on an intact and responding autonomic innervation of the pancreas. RESULTS--There was little evidence of autonomic neuropathy in either the 12 diabetic patients with a history of unawareness of hypoglycaemia or the seven patients with inadequate hypoglycaemic counterregulation. By contrast, in all seven patients with clear evidence of autonomic neuropathy there was no history of unawareness of hypoglycaemia and in six out of seven there was adequate hypoglycaemic counterregulation. Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation were significantly associated (p less than 0.01). The response of plasma pancreatic polypeptide in the diabetic patients with adequate counterregulation but without autonomic neuropathy was not significantly different from that of the controls (change in plasma pancreatic polypeptide 226.8 v 414 pmol/l). The patients with autonomic neuropathy had a negligible plasma pancreatic polypeptide response (3.7 pmol/l), but this response was also blunted in the patients with inadequate hypoglycaemic counterregulation (72.4 pmol/l) compared with that of the controls (p less than 0.05). CONCLUSIONS--Unawareness of hypoglycaemia and inadequate glucose counterregulation during hypoglycaemia are related to each other but are not due to autonomic neuropathy. The blunted plasma pancreatic polypeptide responses of the patients with inadequate hypoglycaemic counterregulation may reflect diminished autonomic activity consequent upon reduced responsiveness of a central glucoregulatory centre, rather than classical autonomic neuropathy.     

Peripheral neuropathy and indomethacin.

A patient with seronegative inflammatory polyarthritis developed a predominantly motorperipheral neuropathy associated with the use of indomethacin. Three other cases of peripheral neuropathy associated with indomethacin treatment have been reported to the Committee on Safety of Medicines. In all cases the neuropathy regressed when indomethacinwas stopped. Peripheral neuropathy should be recognized as a rare complication of indomethacin therapy and considered in the differential diagnosis of a neuropathy accompanyingrheumatoid arthritis.     

Green synthesis of silver nanoparticles by Nigella sativa extract alleviates diabetic neuropathy through anti-inflammatory and antioxidant effects

Green synthesis of silver nanoparticles has gained great interest among scientists. In view of this data, we conducted this study to identify the ameliorative effect of green synthesis of silver nanoparticles using Nigella sativa extract in diabetic neuropathy induced experimentally. In this study, 50 adult male albino rats were used and they were randomly divided into five groups; the first group was the healthy control group, the second group were the diabetic neuropathy diabetic neuropathy induced, Groups (3-6) diabetic neuropathy induced group and treated with silver nanoparticles, Nigella sativa extract and green synthesized silver nanoparticles using Nigella sativa extract respectively. Biochemical parameters including diabetic, inflammatory and antioxidant biomarkers were evaluated. Brain histopathology was also performed. Results revealed substantial rise in glucose, AGE, aldose reductase with insulin reduction in diabetic neuropathy induced group as compared to healthy control. Also, inflammatory markers increased significantly in diabetic neuropathy induced group. A remarkable change in oxidative status was observed in the same group. Furthermore, significant decline in nitrotyrosin level was observed. Regarding gene expression, we found significant down regulation in brain TKr A accompanied by upregulation of nerve growth factor in diabetic neuropathy group comparing with healthy control. Several treatments for diabetic neuropathy remarkably ameliorate all the investigated biomarkers. Histological findings are greatly relied on for the results achieved in this study. Therefore, it can be established that green synthesis of silver nanoparticles in combination with Nigella sativa extract could be a newly neuroprotective agents against inflammation and oxidative stress characterizing diabetic neuropathy through their antidiabetic, anti-inflammatory and anti-oxidants effects.     

High incidence of vincristine-induced neuropathy in lymphomas.

The incidence of vincristine-induced neuropathy was studied in 60 unselected patients, of whom 23 had lymphoma and 37 had other malignant disease. All were treated with vincristine combined with other cytotoxic agents. Fourteen of the patients with lymphoma (61%) developed neuropathy compared with five patients with leukaemia or non-lymphoid cancer (14%), even though all patients received comparable doses of vincristine. The difference between the two groups in the incidence of neuropathy was highly significant. Of the patients who developed neuropathy, 17 did so within the first three months of treatment and seven in the first month. Patients with lymphoma who are receiving vincristine should be observed carfully for symptoms and signs of neuropathy. Vincristine should be withdrawn if progressive neurotoxicity develops.     

STUDIES ON AXOPLASMIC TRANSPORT OF INDIVIDUAL PROTEINS: 1–ACETYLCHOLINESTERASE (AChE) IN ACRYLAMIDE NEUROPATHY

Abstract— The axoplasmic transport rate and distribution of acetylcholinesterase (AChe, EC 3.1.1.7) was studied in the sciatic nerves of normal rats and those with a neuropathy due to acrylamide, by measuring the accumulation of the enzyme proximal to single and double ligatures. The single ligature experiments showed that the apparent transport rate of AChE was decreased in acrylamide neuropathy. The double ligature experiments indicated that only 8.1% of AChE was mobile in normal rat sciatic nerve. The mobility of the enzyme in acrylamide-treated rat sciatic nerves was altered to 11.8%. The absolute transport rate of AChE in normal rat sciatic nerve was 567 mm/24 h, and in acrylamide neuropathy it was decreased to 287 mm/24 h.
The amount of AChE activity transported in normal rat sciatic nerve was 2.64 μmol/24 h. The rats with acrylamide neuropathy showed a decrease in the amount of AChE activity moving in the orthograde direction (2.03 μmol/24 h).
The colchicine-binding properties of tubulin protein from sciatic nerves of normal and acrylamide-treated rats were studied. In rats with acrylamide neuropathy, a marked decrease of 75% in tubulin-colchicine binding was observed.     

MR Neurography in Ulnar Neuropathy as Surrogate Parameter for the Presence of Disseminated Neuropathy

Purpose

Patients with ulnar neuropathy of unclear etiology occasionally present with lesion extension from elbow to upper arm level on MRI. This study investigated whether MRI thereby distinguishes multifocal neuropathy from focal-compressive neuropathy at the elbow.

Methods

This prospective study was approved by the institutional ethics committee and written informed consent was obtained from all participants. 122 patients with ulnar mononeuropathy of undetermined localization and etiology by clinical and electrophysiological examination were assessed by MRI at upper arm and elbow level using T2-weighted fat-saturated sequences at 3T. Twenty-one patients were identified with proximal ulnar nerve lesions and evaluated for findings suggestive of disseminated neuropathy (i) subclinical lesions in other nerves, (ii) unfavorable outcome after previous decompressive elbow surgery, and (iii) subsequent diagnosis of inflammatory or other disseminated neuropathy. Two groups served as controls for quantitative analysis of nerve-to-muscle signal intensity ratios: 20 subjects with typical focal ulnar neuropathy at the elbow and 20 healthy subjects.

Results

In the group of 21 patients with proximal ulnar nerve lesion extension, T2-w ulnar nerve signal was significantly (p<0.001) higher at upper arm level than in both control groups. A cut-off value of 1.92 for maximum nerve-to-muscle signal intensity ratio was found to be sensitive (86%) and specific (100%) to discriminate this group. Ten patients (48%) exhibited additional T2-w lesions in the median and/or radial nerve. Another ten (48%) had previously undergone elbow surgery without satisfying outcome. Clinical follow-up was available in 15 (71%) and revealed definitive diagnoses of multifocal neuropathy of various etiologies in four patients. In another eight, diagnoses could not yet be considered definitive but were consistent with multifocal neuropathy.

Conclusion

Proximal ulnar nerve T2 lesions at upper arm level are detected by MRI and indicate the presence of a non-focal disseminated neuropathy instead of a focal compressive neuropathy.     

CRP、PTH、Alb及Hb水平变化与尿毒症周围神经病变程度的相关性

摘要 目的：探讨C反应蛋白（CRP）、甲状旁腺素（PTH）、血清白蛋白（Alb）及血红蛋白（Hb）水平变化与尿毒症周围神经病变程度的相关性。方法：选取我院2019年4月到2022年4月收治的340例需要进行维持性血液透析治疗的尿毒症患者作为研究对象,依照是否存在周围型神经病变的情况分为非神经病变组（n=132）和神经病变组（n=208）。对比两组患者的临床相关资料,CRP、PTH、Alb及Hb水平变化,其他血清指标变化,并分析CRP、PTH、Alb及Hb水平变化与尿毒症周围神经病变程度的相关性。结果：两组患者高血压患病人数对比无差异（P＞0.05）,两组患者的糖尿病患病人数、血液透析频率以及血液透析时间对比差异显著（P<0.05）;神经病变组患者的CRP、PTH水平明显高于非神经病编组（P＜0.05）,神经病变组患者的Alb、Hb水平明显低于非神经病变组（P＜0.05）;两组患者血浆胆固醇（CHO）、红细胞（RBC）、三酰甘油（TG）、血肌酐（SCr）水平对比无显著差异（P＞0.05）,神经病变组患者血清前白蛋白（PA）、二氧化碳结合力（CO2CP）水平低于非神经病变组,神经病变组患者血清BUN、FBG水平高于非神经病变组（P＜0.05）;Spearman相关分析结果显示：CRP、PTH与尿毒症周围神经病变程度呈正相关（P＜0.05）,Alb、Hb与尿毒症周围神经病变程度呈负相关（P＜0.05）。结论：CRP、PTH、Alb及Hb水平变化与尿毒症周围神经病变程度具有明显关系,可以用于判断尿毒症患者的周围神经病变程度。而且尿毒症周围神经病变患者多数原发疾病为糖尿病,血液透析频率较低,维持血液透析时间较长。     

sRAGE and esRAGE are not associated with peripheral or autonomic neuropathy in type 2 diabetes.

The receptor for glycation end-products RAGE was previously shown to play a central role in the development of diabetic neuropathy. The present study was aimed to investigate, whether plasma levels of the soluble forms of RAGE are associated with neuropathy in type 2 diabetes. One-hundred and eight patients were screened for peripheral and autonomic diabetic neuropathy using standardized screening tests. No differences in the levels of soluble RAGE or the more defined endogenous secretory RAGE were observed in patients categorized into having no, mild, moderate, or severe deficits in the neuropathy disability or symptom score. In bivariate analysis, neither soluble RAGE nor endogenous secretory RAGE correlated with the expiration to inspiration ratio of heart rate variability. In multivariate models, the neuropathy disability score was independently associated with age (beta=0.38, p<0.01), glomerular filtration rate (beta=0.28, p<0.01) and the presence of retinopathy (beta=0.27, p<0.01), while the neuropathy symptom score was associated with age (beta=0.31, p<0.01) and fasting glucose (beta=0.24, p<0.05). The expiration to inspiration ratio of heart rate variability was associated with age (beta=-0.42, p<0.01), the body-mass-index (beta=-0.28, p<0.01) and presence of retinopathy (beta=-0.19, p<0.05). In contrast to classical risk factors, plasma soluble RAGE and endogenous secretory RAGE are not associated with measures of diabetic neuropathy in type 2 diabetes patients.     

Diabetes mellitus and thermoregulation

Diabetes mellitus is accompanied by a variety of alterations in metabolic, cardiovascular, and neuronal function. This paper provides a comprehensive review of the ways in which these pathophysiological aspects of diabetes may impair thermoregulatory function. The influence of diabetic neuropathy and vasculopathy on the control of peripheral blood flow is reviewed and the additional effects of changing levels of blood glucose and insulin are discussed. Both hypoglycaemia and diabetic ketoacidosis are associated with hypothermia, but the reasons for this in ketoacidosis are not clear. Impairment of heat conservation may contribute to and could be a consequence of autonomic neuropathy. The final section of the paper describes a study of our own in which metabolic stability was maintained by infusing insulin intravenously before and during the determination of the thermoregulatory responses to acute cold stress. Under these conditions, there was impairment of reflex vasoconstriction in the limbs of diabetics with neuropathy. This failure to reduce heat loss resulted in half the diabetics with neuropathy shivering in response to moderate cooling, which in some subjects was accompanied by a fall in core temperature. Diabetics without neuropathy and nondiabetics neither shivered nor dropped core temperature.     

Recurrent subacute visual loss presenting in a 52-year-old Caucasian woman with chronic relapsing inflammatory optic neuropathy: a case report

Introduction

Chronic relapsing inflammatory optic neuropathy is a recently described form of recurrent isolated subacute optic neuropathy. The condition is highly responsive to systemic steroid treatment and prone to relapse on steroid withdrawal. A complete work up for demyelination, autoimmune disease and sarcoidosis must be made before considering chronic relapsing inflammatory optic neuropathy.

Case presentation

We describe the case of a 52-year-old Caucasian woman who presented with isolated subacute optic neuropathy. There was no evidence of demyelination, autoimmunity or sarcoidosis. There was an abrupt and prompt response to systemic corticosteroids and a relapse of the condition on steroid withdrawal.

Conclusions

Chronic relapsing inflammatory optic neuropathy requires careful consideration and differentiation from demyelinating optic neuritis and ischemic optic neuropathy since the treatment is different and the outcome without treatment is likely to be poor. The importance of identifying these patients has considerable clinical implications as the condition is highly responsive to steroids.     

Effective Suppression of Acrylamide Neurotoxicity by Lithium in Mouse

The primary objective of this investigation was to assess the neuroprotective efficacy of lithium in an acrylamide (ACR)-induced neuropathy model in mice. In this study, Kunming male mice were administered ACR (25 mg/kg bw, i.p. once a day) with or without lithium (25 mg/kg bw, i.p. once a day) for 2 weeks. All ACR-administered mice exhibited severe symptoms of neuropathy. We found that treatment with lithium effectively alleviated behavioral deficits in animals elicited by acrylamide. Interestingly, the reduction of hippocampal neurogenesis resulting from ACR injection was promoted by administration of lithium. Further, lithium treatment significantly offset ACR-induced depletion in p-GSK-3β (Ser9) levels in hippocampus. Collectively our findings suggest the propensity of lithium to attenuate ACR-induced neuropathy. Further studies are necessary to understand the precise molecular mechanism by which the lithium attenuates neuropathy. Nevertheless, our data clearly demonstrate the beneficial effects of lithium on ACR-induced neuropathy in mice and suggest its possible therapeutic application as an adjuvant in the management of other forms of neuropathy in humans.     

Diabetic autonomic neuropathy and iritis: an association suggesting an immunological cause.

Of 47 insulin requiring diabetics aged 21-40 years with autonomic neuropathy (heart rate variability less than 10), 14 had previously developed iritis. In all except two cases the iritis preceded the autonomic symptoms. The autonomic neuropathy was very severe, 10 patients having two or more characteristic symptoms. Ten of the patients with iritis were women. The association of iritis (itself an immune disorder) with severe symptomatic autonomic neuropathy raises the possibility of an underlying immunological basis for autonomic neuropathy.     

Measurement of the residual urine index in insulin-dependent and non-insulin dependent diabetic men with and without neuropathy

Value of the residual urine index was evaluated in 40 individuals both insulin-dependent (IDDM) and non-insulin dependent (NIDDM) diabetic male patients with and without an objective evidence of neuropathy and in 20 age matched non-diabetic men serving as controls using post void bladder ultrasonographic technique. These studies revealed striking results in the neuropathic group. Both IDDM and NIDDM diabetic patients with neuropathy exhibited a significant (P < 0.005) increase in residual-volume in comparison with the controls of the same age group and a direct correlation between residual urine retention and neurogenic bladder was found to be established thus suggesting a generalized massive hypotonia of the bladder in these patients. However, non of the two types of non-neuropathic diabetic patients showed significant difference in the above-mentioned parameters compared to that their respective controls. A non-significant association in the values of the study parameters between insulin dependent and non-insulin dependent diabetic men (with and without neuropathy) was also observed. These findings thus suggest a probable neuropathic involvement in the pathway of urinary tract in both IDDM and NIDDM diabetic men with neuropathy. The greater impairment of the values of residual urine index in these patients may be due to overall greater severity of neuropathy with sympathetic as well as parasympathetic damage irrespective of their type of diabetes.     

Cardiac Denervation in Diabetes

Evidence for vagal denervation of the heart as a feature of diabetic autonomic neuropathy has been obtained by monitoring beat-to-beat variation in heart rate. Nine diabetics with autonomic neuropathy were assessed; each showed a marked reduction or absence of beat-to-beat variation in comparison with controls. Beat-to-beat variation in normal subjects is abolished by parasympathetic blockade but unaffected by sympathetic blockade. These findings suggest that spontaneous vagal denervation of the heart was present in the cases studied. Measurement of beat-to-beat variation provides a simple test whereby cases of autonomic neuropathy can be screened for cardiac involvement.     

Medial arterial calcification and diabetic neuropathy.

X-ray examinations of the feet, knees, and hands were performed on 20 diabetics with severe neuropathy and 20 diabetics with no evidence of neuropathy but with a similar mean age and duration of diabetes. All were under 53 years old with no clinical evidence of peripheral vascular disease. Medial arterial calcification was much more common and extensive in the patients with neuropathy, occurring in the feet in 15 and in the hands in eight compared with in four (p less than 0.001) and none (p less than 0.001) of the controls respectively. Although there was some correlation between calcification and both proteinuria (p less than 0.05) and proliferative retinopathy (p less than 0.02), the association between calcification and neuropathy (p less than 0.001) was much stronger. Neuropathy, with sympathetic denervation of the smooth muscle of the tunica media, may be important in the aetiology of medial arterial calcification.     

Exogenous neuritin treatment improves survivability and functions of Schwann cells with improved outgrowth of neurons in rat diabetic neuropathy

Pathogenesis and treatment for diabetic neuropathy are still complex. A deficit of neurotrophic factors affecting Schwann cells is a very important cause of diabetic neuropathy. Neuritin is a newly discovered potential neurotrophic factor. In this study, we explored the effect of exogenous neuritin on survivability and functions of diabetic Schwann cells of rats with experimental diabetic neuropathy. Diabetic neuropathy was induced in rats. 12‐week diabetic rats contrasted with non‐diabetic normal rats had decreased levels of serum neuritin and slowed nerve conduction velocities (NCVs). Schwann cells isolated from these diabetic rats and cultured in high glucose showed reduced cell neuritin mRNA and protein and supernatant neuritin protein, increased apoptosis rates, increased caspase‐3 activities and progressively reduced viability. In contrast, exogenous neuritin treatment reduced apoptosis and improved viability, with elevated Bcl‐2 levels (not Bax) and decreased caspase‐3 activities. Co‐cultured with diabetic Schwann cells pre‐treated with exogenous neuritin in high glucose media, and diabetic DRG neurons showed lessened decreased neurite outgrowth and supernatant NGF concentration occurring in co‐culture of diabetic cells. Exogenous neuritin treatment ameliorated survivability and functions of diabetic Schwann cells of rats with diabetic neuropathy. Our study may provide a new mechanism and potential treatment for diabetic neuropathy.     

Laser Doppler Flare Imaging and Quantitative Thermal Thresholds Testing Performance in Small and Mixed Fiber Neuropathies

IntroductionSmall fiber neuropathy might be a part of typical mixed small and large fiber neuropathy, or a distinct entity, affecting exclusively small nerve fibers.ObjectivesExplore the utility of small nerve fiber testing in patients with clinical presentation suggesting small fiber neuropathy, with and without evidence for concomitant large fiber neuropathy.MethodsPatients attending the neuromuscular clinic from 2012 to 2015 with a clinical presentation suggesting small nerve fiber impairment, who had Laser Doppler flare imaging (LDI_Flare) and quantitative thermal testing (QTT) were evaluated for this study. Patients with clinical or electrophysiological evidence for concomitant large fiber neuropathy were not excluded.ResultsThe sensitivities of LDI_Flare, cooling and heat threshold testing were 64%, 36%, and 0% respectively for clinically highly suggestive small fiber neuropathy, 64%, 56%, and 19% respectively for mixed fiber neuropathy, and 86%, 79%, and 29% respectively for diabetic mixed fiber neuropathy.DiscussionLDI_Flare and cooling thresholds testing are non-invasive small nerve fiber testing modalities, with moderate performance in patients with small and mixed fiber neuropathy, and excellent performance in diabetic mixed fiber neuropathy.     

Immediate heart-rate response to standing: simple test for autonomic neuropathy in diabetes.

The immediate heart-rate response to standing was measured in 22 normal controls and 25 patients with diabetes, 15 of whom had autonomic neuropathy. The response in the controls and patients without autonomic neuropathy was characteristic and consistent, with tachycardia maximal at around the 15th beat and relative bradycardia maximal at around the 30th beat. The diabetics with autonomic neuropathy, however, showed a flat response. In three controls the response was abolished with intravenous atropine but not with propranolol, showing that it is mediated through the vagus. A simplified test using routine ECGs and measuring the R-R interval at beats 15 and 30 with a ruler is easily performed as an outpatient procedure and may be used as a measure of autonomic function in diabetes.