Blood flow patterns in painful diabetic neuropathy

Summary Peripheral blood flow is known to be qualitatively increased in diabetic patients with neuropathy. We have measured the actual blood flow in the feet of diabetic patients with neuropathy using non-invasive mercury strain gauge plethysmography and Doppler sonogram techniques and shown that it is increased on average five times above normal at an ambient temperature of 20 °–22 °C. Moreover, reduction of this high flow by sympathetic arousal stimuli proved possible in those with severe painful neuropathy contrasting strongly with failure to reverse it in those with severe non-painful sensory neuropathy. Reduction of blood flow was associated with reduction in neuropathic pain. We studied 22 diabetic patients with severe sensory neuropathy and eight with painful neuropathy. High resting foot blood flows were demonstrated in both groups with neuropathy. The big toe flow in those with severe sensory neuropathy was 29.3±9.2 ml · min^–1 · 100 ml^–1 (mean±SD) and in the painful neuropathy group, 25.9±7.5, compared with 5.2±2.4ml · min^–1 · 100ml^–1 in the non-diabetic control subjects (p<0.001). High foot skin temperatures were also recorded in the groups with neuropathy, reflecting the high blood flow. The subjects with painful neuropathy retained the ability to constrict peripheral blood vessels in response to arousal stimuli, and reduce peripheral flow on average by 32% compared with the patients with sensory neuropathy who responded on average by only 10%. The demonstration of a peripheral sympathetic defect, responsible for the high blood flow and the potential reversal of such flow in painful neuropathy may be important in our further understanding of the aetiology of such pain and its treatment.     

Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy

Summary Clinical, electrophysiological and ultrastractural morphometric observations were made in 5 diabetic non-neuropathic patients, 5 diabetic patients with mild neuropathy and 11 diabetic patients with severe neuropathy. Capillary abnormalities were assessed in simultaneous nerve, muscle and skin biopsies and compared with results from 6 age-matched, non-diabetic control subjects.Nerve capillaries demonstrated markedly greater pathology than skin and muscle capillaries. Endoneurial capillary density was significantly reduced in severely neuropathic diabetic patients (p<0.01) when compared with control subjects. Capillary basement membrane (p<0.002), endothelial cell (p<0.003) and total diffusion barrier (endothelial cell, pericyte, basement membrane) (p<0.001) thickness were significantly increased, and oxygen diffusing capacity was significantly reduced (p<0.001) in the nerves of patients with severe diabetic neuropathy when compared to control subjects. Endothelial cell profile number and luminal perimeter were significantly increased in asymptomatic (p<0.01), (p<0.05) and severely neuropathic (p<0.001), (p<0.05) diabetic patients respectively. However, endothelial cell outer perimeter, a measure of capillary size, showed no significant increase in diabetic patients when compared with control subjects. An association was observed between neurophysiological and neuropathological measures of neuropathic severity. There was no significant correlation between the duration of diabetes and HbA₁ levels with capillary pathology or with neuropathic severity. Very few abnormalities of muscle and skin correlated with neuropathic severity. However, all measures of nerve capillary pathology correlated significantly with neurophysiological and neuropathological measures of neuropathic severity.     

维生素D缺乏与糖尿病周围神经病变

糖尿病周围神经病变（DPN）患者中普遍存在维生素D缺乏的现象.1,25（OH）2D3作为维生素D的活性形式,通过与细胞内的维生素D受体（VDR）结合发挥生物学作用.已有研究证明DPN与维生素D缺乏之间具有相关性.维生素D缺乏导致DPN的机制尚不完全清楚,但有资料证实维生素D缺乏可导致神经系统发育障碍、神经损伤及神经变性性疾病,减弱抗炎作用,促进动脉粥样硬化发展,损害胰岛β细胞功能及上调基质金属蛋白酶水平,进一步导致DPN的发生和发展.     

Hypoxic neuropathy: relevance to human diabetic neuropathy

Summary Clinical and neurophysiological studies were conducted in 47 patients with chronic obstructive airways disease and compared with 46 age-matched control subjects. Symptomatic neuropathy was reported in 13% and ankle jerks were absent in 45% of hypoxic patients. Peroneal and median nerve conduction velocities and median and sural sensory nerve amplitudes were significantly reduced in hypoxic patients (p<0.01). Six hypoxic patients underwent biopsy of the sural nerve, soleus muscle and overlying skin. Nerve glucose, sorbitol, fructose and myo-inositol concentrations were normal. Detailed light and electronrmicroscopy revealed both nerve fibre and microvascular pathology. Segmental demyelination (32%) and unmyelinated fibre degeneration were found to be prominent lesions. The sural nerve perineurium was thickened due to an increase in the number of perineurial lamellae and an increase in intraperineurial space. Basement membrane thickening was observed in capillaries of nerve, muscle and skin. Endothelial cell hyperplasia and hypertrophy were observed in nerve and muscle capillaries but not in skin capillaries. In conclusion, this study has provided neurological, neurophysiological and neuropathological evidence of a neuropathy in hypoxic patients with chronic obstructive airways disease. These findings may be of relevance to some aspects of the aetiology of human diabetic neuropathy.     

Correlations between nerve function and tissue oxygenation in diabetic patients: further clues to the aetiology of diabetic neuropathy?

Summary Transcutaneous oxygen, laser Doppler flowmetry, peroneal nerve motor conduction velocity and skin temperature were assessed in both legs of 34 diabetic patients, who had a mean age of 41 (range 29–77) years, and diabetes duration of 21 (3–34) years. Transcutaneous oxygen significantly correlated with peroneal nerve motor conduction velocity (r=0.59 p<0.001) and laser Doppler flowmetry (r=0.7 p<0.001). Laser Doppler flowmetry correlated weakly with peroneal motor conduction velocity, (r=0.34 p<0.05). In each patient the leg with the higher transcutaneous oxygen (mean 70.2±9.3 (SD) mmHg) had a significantly higher peroneal motor conduction velocity (45.3±7.1 vs 41.5± 6.3 m/s, p<0.01), than the leg with the lower transcutaneous oxygen (61.0±11.9 mm Hg), though no difference in skin temperature was observed, 31.4±0.4 vs 31.1±0.5°C. We then assessed the potential for reversibility of conduction velocity deficits in ten non-diabetic patients, aged 59 (52–77) years, undergoing unilateral femoro-popliteal bypass, measuring transcutaneous oxygen, peroneal nerve motor conduction velocity and skin temperature pre- and 6 weeks post-surgery. In the control leg (unoperated) there was no significant change in transcutaneous oxygen (63.2±8.8 vs 63.0±4.6 mm Hg), peroneal nerve motor conduction velocity (45.1±7.8 vs 43.4±7.2 m/s) or skin temperature (30.8±1.3 vs 30.2±1.2°C) after surgery (all NS). In the operated leg, transcutaneous oxygen increased from 59.3±10.7 to 70.7±7.2 mm Hg (p<0.01), and peroneal nerve motor conduction velocity from 42.6±6.1 to 46.7±3.2 m/s (p<0.01), but skin temperature was unchanged 30.3±0.4 vs 30.4± 1.3°C (NS). These studies provide further evidence that peripheral nerve function is associated with tissue hypoxia and that improving tissue oxygenation can significantly improve nerve conduction over a short period of time.     

肌电电生理诊断糖尿病早期周围神经病变的敏感指标探讨

本文报道了１７１例糖尿病患者通过肌电图电生理检查，测定运动和感觉传导速度及胫神经Ｈ反射的结果，并分析了临床症状，发现糖尿病周围神经病１１６例（６７．８％），其中单纯Ｈ反射异常２７例，神经传导异常兼有或无Ｈ反射异常８９例，提出了诊断糖尿病性周围神经病电生理检查最敏感的指标，并探讨了神经传导与年龄、病程、空腹血糖、果糖胺及ＨｂＡｌｃ之间的相互关系。     

Endoneurial microvascular pathology in feline diabetic neuropathy

Endoneurial capillaries in nerve biopsies from 12 adult diabetic cats with varying degrees of neurological dysfunction were examined for evidence of microvascular pathology and compared to nerves obtained at necropsy from 7 adult non-diabetic cats without clinical evidence of neurological dysfunction. As reported previously [Mizisin, A.P., Nelson, R.W., Sturges, B.K., Vernau, K.M., LeCouteur, R.A., Williams, D.C., Burgers, M.L., Shelton, G.D., 2007. Comparable myelinated nerve pathology in feline and human diabetes mellitus. Acta Neuropathol. 113, 431-442.], the diabetic cats had elevated glycosylated hemoglobin and serum fructosamine levels, decreased motor nerve conduction velocity and compound muscle action potential (CMAP) amplitude, and markedly decreased myelinated nerve fiber densities. Compared to non-diabetic cats, there was a non-significant 26% increase in capillary density and a significant (P<0.009) 45% increase in capillary size in diabetic cats. Capillary luminal size was also significantly (P<0.001) increased, while an index of vasoconstriction was significantly decreased (P<0.001) in diabetic cats compared to non-diabetic controls. No differences in endothelial cell size, endothelial cell number or pericyte size were detected between non-diabetic and diabetic cats. In diabetic cats, basement membrane thickening, seen as a reduplication of the basal lamina, was significantly (P<0.0002) increased by 73% compared to non-diabetic controls. Regression analysis of either myelinated nerve fiber density or CMAP amplitude against basement membrane size demonstrated a negative correlation with significant slopes (P<0.03 and P<0.04, respectively). These data demonstrate that myelinated nerve fiber injury in feline diabetic neuropathy is associated with microvascular pathology and that some of these changes parallel those documented in experimental rodent and human diabetic neuropathy.     

黄芩甙治疗糖尿病周围神经病变的初步观察

目的观察黄芩甙对醛糖还原酶（AR）活性的抑制作用及其对糖尿病神经病变的疗效。方法74例糖尿病患者随机分为黄芩甙治疗组和对照组,治疗组每天服黄芩甙3g。结果黄芩甙治疗后患者红细胞AR活性显著降低（1．29±0．64U／gHbvs2．42±0．85U／gHb,P＜0．01）;黄芩甙缓解神经病变症状总有效率为583％,明显高于对照组（3．3％,P＜0．01）;治疗后黄芩甙组神经传导速度趋于稳定,部分项目略有改善,而对照组则呈进行性恶化趋势,两组腓总神经、胫神经传导速度有显著性差异,分别为31．4±6．1m／svs269±5．3m／s（P＜0．05）和31．8±5．2m／svs26．5±4．8m／s（P＜0．05）,黄芩甙组的腓总神经、医神经末端潜伏期明显绍短,分别为5．00±0．64m／svs5．60±0．56m／s（P＜0．05）和5．10±0．58m／svs5．60±0．57m／s（P＜0．05）,正中神经和尺神经的感觉神经动作电位波幅也显著提高（P＜0．05）。未见明显不良反应及肝肾毒性。结论黄芩甙在体内具有明显的AR活性抑制作用,可有效的缓解糖尿病周围神经病变的临床症状,改善其神经传导速度,从而有助于防止糖尿病神经病变的发生与发展。     

Painful diabetic neuropathy.

Chronic painful diabetic neuropathy causes symptoms that can last for many years and severely impair the quality of life of affected patients. This review describes the epidemiology, pathophysiology and treatment of chronic neuropathic pain. Particular emphasis is placed on a comprehensive review of the management of painful symptoms through a detailed review of the published literature using a variety of databases particularly Medline and EMBASE.     

痛性糖尿病周围神经病变的临床治疗进展

痛性糖尿病周围神经病变(PDPN)是一种常见的较难治疗的糖尿病并发症,疼痛症状常导致患者抑郁和生活质量下降.治疗主要是针对潜在疾病,要控制好血糖,防止神经病变进展.缓解疼痛是治疗糖尿病周围神经病变(DPN)的重点与难点.目前疗法主要包括药物和物理治疗.药物主要有抗氧化剂、神经营养因子、抗抑郁药、抗癫痫药、抗心律失常药、麻醉类镇痛药及中药等.新一代药物不良反应较少,为治疗PDPN提供了新的选择.本文就其治疗的进展及机制作一综述.     

Autonomic neuropathy and diabetic foot ulceration

Autonomic function was studied in three groups of insulin-dependent diabetic patients. Heart rate changes during deep breathing and on standing were significantly less in 28 patients with a recent history of foot ulceration compared with 40 patients with peripheral neuropathy but without ulceration (p less than 0.001) and 54 patients without neuropathy (p less than 0.001). Sympathetic function was assessed in 36 of these patients from peripheral arterial diastolic flow patterns obtained by Doppler ultrasound measurements and expressed as the pulsatility index (PI). Patients with a history of ulceration (n = 10) showed considerably increased diastolic flow (PI = 4.28 +/- 0.53, mean +/- S.E.M.) compared with 12 neuropathic patients with no history of ulceration (PI = 7.80 +/- 0.68, p less than 0.002) and 14 patients without neuropathy (PI = 9.55 +/- 0.89, p less than 0.002). Severely abnormal autonomic function occurs in association with neuropathic foot ulceration, but patients without ulcers have lesser degrees of autonomic neuropathy, thus a causal relationship has not been established.     

氧化应激与糖尿病神经病变

氧化应激与糖尿病神经病变的发生、发展密切相关,晚期糖基化终末产物、多元醇通路和蛋白激酶C激活等途径均可增加体内氧化应激反应导致糖尿病神经病变的发生、发展。应用α-硫辛酸,维生素C、E和褪黑素等抗氧化治疗将为糖尿病神经病变的防治提供新的思路。     

Cell-mediated immunity and symptomatic diabetic autonomic neuropathy

T lymphocytes have been implicated in the nerve damage observed in allergic experimental neuritis and in idiopathic polyneuritis. Symptomatic autonomic neuropathy in long-standing Type 1 diabetes is a rare and unexplained complication, and some preliminary evidence has suggested a pathogenetic role for the immune system. We have measured levels of activated T lymphocytes in 18 Type 1 diabetic patients with symptomatic autonomic neuropathy and in 16 matched patients with uncomplicated Type 1 diabetes. Purified T lymphocytes from peripheral blood were stained with a fluorescein-labelled monoclonal antibody directed to the activation marker HLA-DR and counted under UV microscopy. Percent DR positive T lymphocytes were significantly raised in the patients with autonomic neuropathy when compared with long-standing uncomplicated diabetic patients (8.2 +/- 4.2 vs 4.9 +/- 3.3%, p less than 0.01). This finding lends support for a role of the immune system in the development of autonomic neuropathy.     

2型糖尿病患者周围神经病变危险因素分析

目的 探讨T2DM住院患者糖尿病周围神经病变（DPN）患病率及危险因素. 方法 选取T2DM住院患者205例,以多伦多临床评分系统（TCSS）评分作为DPN诊断标准,分为DPN组和无DPN（NDPN）组,比较两组各项指标. 结果 DPN患病率43.9％.DPN组年龄（57.76±12.50）vs（49.50±13.28）岁]、病程[（8.12±2.50）vs（5.67±1.99）年]、体重[（62.50±10.46） vs （67.03±13.43）kg]、DBP[（82.79±13.69）vs（86.98±12.18） mmHg]、BUN[（10.15±1.52）vs（41.35±5.66）μmol/L]、Scr[（102.79±61.56）vs（74.61±34.26）μmol/L]、UAlb/Cr[（211.66±26.78）vs（44.21±9.77）mg/24 h]和DR患病率[41（45.5％） vs 20（17.4％）]与NDPN组比较差异有统计学意义（P＜0.01）.Logistic多元回归分析显示,年龄、病程、UAlb/Cr、合并DR与DPN发生呈正相关. 结论 年龄、病程、UAlb/Cr、合并DR可能是T2DM住院患者发生DPN的危险因素.     

A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population

Summary A cross-sectional multicentre study of randomly selected diabetic patients was performed using a standardised questionnaire and examination, to establish the prevalence of peripheral neuropathy in patients attending 118 hospital diabetes clinics in the UK. Vibration perception threshold was performed in two centres to compare with the clinical scoring systems. A total of 6487 diabetic patients were studied, 53.9% male, median age 59 years (range 18– 90 years), 37.4% Type 1 (insulin-dependent) diabetes mellitus, with a median duration of diabetes 8 years (0–62 years). The overall prevalence of neuropathy was 28.5% (27.4– 29.6 %) (95 % confidence interval) in this population. The prevalence in Type 1 diabetic patients was 22.7% (21.0– 24.4 %) and in Type 2 (non-insulin-dependent) diabetic patients it was 32.1 % (30.6–33.6 %). The prevalence of diabetic peripheral neuropathy increased with age, from 5% (3.1– 6.9 %) in the 20–29 year age group to 44.2 % (41.1–47.3 %) in the 70–79 year age group. Neuropathy was associated with duration of diabetes, and was present in 20.8 % (19.1–22.5 %) of patients with diabetes duration less than 5 years and in 36.8 % (34.9–38.7 %) of those with diabetes duration greater than 10 years. Mean vibration perception threshold measured at the great toe was 21.1±13.5 SD volts and correlated with the neuropathy disability score, r=0.8 p<0.001. In conclusion, diabetic peripheral neuropathy is a common complication associated with diabetes. It increases with both age and duration of diabetes, until it is present in more than 50% of Type 2 diabetic patients aged over 60 years. An increased awareness of the high prevalence of peripheral neuropathy, especially in older patients, should result in improved screening programmes in order to reduce the high incidence of neuropathic diabetic foot ulceration.     

乙酰左卡尼汀治疗成人糖尿病周围神经病变的有效性:系统评价和网状Meta分析

目的应用网状Meta分析,比较乙酰左卡尼汀(ALC)与其他常用口服药物治疗糖尿病周围神经病变(DPN)患者的疗效。方法检索中英文电子数据库从建库至2020年2月的文献,纳入包含以下1种或多种药物,包括ALC、α-硫辛酸(ALA)、依帕司他、甲钴胺、胰激肽原酶(口服单药疗法),治疗成人DPN的已发表随机对照试验(RCT)。以神经传导速度(NCV)为主要结局指标,次要结局指标包括波幅、神经症状和体征、疼痛等。采用贝叶斯方法(随机效应模型)对纳入的研究进行网状Meta分析,同时估计各个药物疗效的排序概率,计算其累积排序概率图下面积(SUCRA)。结果最终55项RCT纳入网状Meta分析,包括6473例患者。所有纳入研究均含2个对比组,包括4种治疗药物(ALC、ALA、依帕司他、甲钴胺),其中,涉及ALC的研究为3项(2项对比安慰剂、1项对比甲钴胺)。与甲钴胺相比,ALC可改善正中感觉神经NCV[MD为4.0(95%CI为0.1~7.9)m/s];而在其他神经相关的NCV改善上,尽管从排序结果看,相对于其他常用口服阳性药物,ALC可能在改善正中感觉神经(SUCRA为91.6%)、尺运动神经(SUCRA为69.3%)和尺感觉神经(SUCRA为77.8%)NCV更优;但相对效应值并未发现ALC与其他药物单药治疗有明显差异。结论在DPN治疗中,ALC可能具有改善感觉神经和疼痛的疗效优势,在其他结局上与其他常用口服药物疗效相似。     

高同型半胱氨酸血症与糖尿病周围神经病变的关系

目的了解同型半胱氨酸（Hcy）在2型糖尿病周围神经病变（DPN）患者血浆中的表达水平,干预Hcy表达观察其对DPN的影响。方法200名DPN患者（DPN＋组）和200名无DPN患者（DPN-组）,均检测血浆Hcy水平,将高水平Hcy患者随机分成两亚组。干预亚组给予叶酸、维生素B6,对照亚组不给予干预治疗,3个月后比较各组Hcy水平,并通过临床和电生理方法评估两组神经病变的改变。结果DPN＋组中高Hcy血症患者占40%,其Hcy水平明显高于DPN-组（P〈0.05）。经治疗后高Hcy患者Hcy水平明显下降（P〈0.01）,神经病变症状和神经传导速度与对照组比较也明显改善（P〈0.05）。结论高Hcy为DPN危险因素,有效干预高同型半胱氨酸血症有助于改善神经病变。     

Painful myocardial infarction in severe diabetic autonomic neuropathy

Summary Two cases are reported of painful myocardial infarction in diabetics with severe autonomic neuropathy confirmed by abnormal autonomic function tests. Painless myocardial infarction in diabetics has traditionally been attributed to damage of cardiac pain fibres by autonomic neuropathy but other factors such as microangiopathy in the myocardium may be responsible. It may simply be that diabetics come into hospital more often for other reasons and a silent myocardial infarction diagnosed incidentally.     

Vascular factors in diabetic neuropathy

Summary Despite considerable research we still do not have a comprehensive explanation for the pathogenesis of diabetic neuropathy. Although chronic hyperglycaemia is almost certainly involved, it is not known whether the primary pathology is metabolic, microvascular, or an interaction between the two. Hyperglycaemia-induced polyol pathway hyperactivity associated with nerve sorbitol accumulation and myo-inositol depletion may play a part in the genesis of diabetic neuropathy. The case for microvascular disease in diabetic neuropathy is now strong. Fibre loss in human sural nerve is multifocal, suggesting ischaemia. The degree of vessel disease has been related to the severity of neuropathy. People with chronic obstructive pulmonary disease develop the so called hypoxic neuropathy in which similar microvascular changes occur as in diabetic neuropathy. In rats with experimental diabetic neuropathy nerve blood flow is reduced and oxygen supplementation or vasodilator treatment improved the deterioration in conduction velocity and nerve blood flow. Similarly, in human diabetic neuropathy, there is impaired nerve blood flow, epineurial arterio-venous shunting and a reduction in sural nerve oxygen tension. At what stage during the development of nerve damage these changes occur is yet to be determined.Abbreviations RICF resistance to ischaemic conduction failure