Ischemia-reperfusion injury of peripheral nerve in experimental diabetic neuropathy

The pathogenesis of human diabetic neuropathy likely involves the interplay of hyperglycemia, ischemia, and oxidative stress. Mild-moderate ischemia-reperfusion to streptozotocin (STZ)-induced diabetes results in florid fiber degeneration in diabetic but not in normal nerves. Uncertainty exists as to the influence of duration of diabetes on this susceptibility. We therefore studied diabetic tibial and sciatic nerves using a rat ischemia-reperfusion (IR) model after 1 month and 4 months of diabetes utilizing electrophysiological, behavioral, and neuropathological methods. Electrophysiological abnormalities were present in 1-month diabetic rats (D) and persisted over 4 months. Behavioral scores were decreased markedly at 4 months (p<0.05). Endoneurial edema and ischemia fiber degeneration (IFD) were observed at both the 1-month (p<0.01 and p<0.001) and 4-month (p<0.001) durations in diabetic nerves, whereas only mild or no damage was observed in age-matched control nerves. These findings demonstrate that STZ-induced diabetes exacerbates the morphological and electrophysiological pathology in peripheral nerve to IR injury both in the early timepoint of 1 month and late timepoint of 4 months, although there was a gradation of injury, which is more severe at the later timepoint. Reperfusion exaggerated morphological pathology in 1-month STZ-induced diabetic peripheral nerve.     

Identification of dystrophic sympathetic axons in experimental diabetic autonomic neuropathy

Markedly dilated dystrophic post-ganglionic sympathetic axons have been identified by dopamine-β-hydroxylase immunohistochemistry in the paravascular ileal mesenteric nerves of rats with chronic streptozotocin diabetes. Many axons contained multiple dilatations with interposed axonal segments of near normal dimensions. These axonal abnormalities were absent in control animals. The time course of the development of the axonopathy and its distribution in the alimentary tract correlate with quantitative ultrastructural findings previously reported in this system.     

Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab)

NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions.     

Gabapentin in acute painful diabetic neuropathy

Sir, Acute painful diabetic neuropathy (APDN) is an uncommon syndrome originally recognized by Ellenberg (1974) and termed ‘diabetic neuropathic cachexia’. It has been described in diabetic patients and also in females with diabetes and anorexia nervosa (Steele et al., 1987). Its clinical features consist in an unremitting burning pain in the lower limbs, which is more troublesome at night (Thomas and Griffin, 1995). We present the case of a woman with APDN who improved and became asymptomatic with low doses of gabapentin.     

Local activation of the complement system in endoneurial microvessels of diabetic neuropathy

Quantitative immunocytochemical analysis of complement proteins (CP) was performed on sural nerve biopsies from 15 patients with diabetic neuropathy (DN) and 18 nondiabetic patients with other forms of chronic neuropathy (ON). The mean age of the patients and the pathological severity of the neuropathy were similar in both groups. The percentage of patients that expressed strongly immunoreactive CP in the walls of endoneurial microvessels was significantly greater in DN than in ON for all proteins tested. C3d neoantigen was expressed in 100% of DN cases compared with 17% of ON; and membrane attack complex (MAC), C5b-9 neoantigen, in 93% of DN and 17% of ON. In the cases with DN, 81% of endoneurial microvessels, as identified by the endothelial marker, Ulex europaeus, contained C5b-9 neoantigen deposits, compared with 22% in those of ON, and the staining in DN was significantly more intense. Expression of the neoantigens of C3d and C5b-9 in nerve implies local activation of the complement system. In DN, activation of the complement pathway and formation of the MAC could injure blood vessels and adversely affect the circulation in the endoneurium. Received: 27 November 1998 / Revised, accepted: 16 April 1999     

Acute painful diabetic neuropathy precipitated by strict glycaemic control

Summary A case of acute painful diabetic neuropathy that followed the establishment of strict glycaemic control using continuous subcutaneous insulin infusion is described. Sural nerve biopsy shortly after the onset of the acute painful syndrome showed no evidence of active nerve fibre degeneration; instead, the appearances were those of a chronic neuropathy with prominent regenerative activity. The suggestion is made that adequate diabetic control promoted regeneration and that the pain may have been related to the ectopic generation of impulses in regenerating axon sprouts.The image analysis equipment was purchased with the help of financial grants from Ciba Geigy Ltd., Basel, and the Central Equipment Fund of London University. The electron microscope was provided by the Medical Research Council. J. G. L. is a Pfizer Research Fellow     

应用外周神经减压术治疗痛性糖尿病神经病

目的探讨外周神经减压术治疗痛性糖尿病神经病的疗效。方法应用腓总神经、腓深神经及胫后神经三处外周神经减压术治疗28例临床表现为双下肢对称性疼痛的痛性糖尿病神经病患者，并进行回顾性分析。结果36％（10例）患者术后疼痛明显缓解，61％（17例）患者症状缓解，3％（1例）患者症状无变化。结论应用外周神经减压术，可有效帮助痛性糖尿病神经病患者缓解疼痛。     

Epineurial microvasculitis in proximal diabetic neuropathy

Amongst the focal and multifocal neuropathies that are associated with diabetes mellitus one of the most common is a proximal predominantly motor lower limb neuropathy. Recent evidence has indicated that, at least in a proportion of cases, this may have an inflammatory basis. We have examined a consecutive series of 15 cases of proximal diabetic neuropathy (diabetic amyotrophy). These were characterized by proximal pain and asymmetric proximal or generalized lower limb muscle weakness, associated in some cases with radicular sensory involvement. Two-thirds of the patients had an accompanying distal symmetric sensory polyneuropathy. Biopsy of the intermediate cutaneous nerve of the thigh, a sensory branch of the femoral nerve, showed epineurial microvasculitis in 3 patients and nonvasculitic epineurial inflammatory infiltrates in another case. In a further case, microvasculitis was found in both in the sural nerve and a quadriceps muscle biopsy specimen. The detection of inflammatory changes appeared to be correlated with the occurrence of sensory radicular involvement. Whether similar changes are present in muscle nerves in this predominantly motor syndrome requires further study. Nevertheless, the present observations confirm the view that secondary vasculitic or other inflammatory reactions may contribute to some forms of diabetic neuropathy.

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Received: 16 June 1997 Received in revised form: 29 October 1997 Accepted: 6 November 1997     

糖尿病性周围神经病患者的神经电图改变

目的 观察糖尿病性周围神经病（DPN）患者神经电图的改变。方法 对78例DPN患者进行神经电图检查,包括运动神经传叶速发（MCV）、感觉神经传导速度（SCV）和F波检查。结果 共检查78例患者的468条神经,其中MCV减慢166条,MCV减慢合并远端潜伏期延长39条,异常率43．8％;SCV减慢175条,末引出电位75条,SCV减慢兼远端潜伏期延长26条,异常率58．9％．检查102条神经的F波,其中异常66条,异常率为64．7％,12条神经（11．8％）F波时间离散度增加。结论 神经电图是诊断DPN的敏感及特异性的检查,多个参数相结合有助于提高阳性检出率。     

Effects of uridine in the treatment of diabetic neuropathy: an electrophysiological study

The authors performed a controlled double-blind neurophysiological study (uridine vs placebo) in 40 diabetic patients with peripheral neuropathy. Twenty subjects were treated with uridine and 20 with placebo. The neurophysiological evaluation consisted of a study of the MCV of the median nerve, the common Peroneal, the posterior Tibial, the SCV of the radial nerve, the median and the sural as well as the amplitudes of the motor and sensory responses. The nerves examined were on the dominant side. The evaluations were performed at baseline and after 60, 120, 180 days of therapy with a follow up control after 90 days from the completion of therapy. No statistically significant modifications were observed in the placebo group. In the drug group, the neurophysiological parameters improved significantly from the 120th day post therapy compared with baseline and were maintained through to follow up. The authors discuss the results which demonstrated that treatment with uridine can bring about a neurophysiological improvement in peripheral nerves.     

肌电图对糖尿病周围神经病的诊断价值

目的：探讨神经肌电图在糖尿病性周围神经病（DPN ）诊断中的应用价值。方法：选择我院2012年1月～2014年6月收治的200例DPN患者的临床资料,分析肌电诱发电位仪对患者的相关神经进行检测的结果。结果：在200例DPN患者中,神经电图总异常率高达71．5％。且随着病程的延长,其EM G异常率的发生逐渐增加。病程在1年以内的患者EM G异常率为40．8％,而病程在10年以上者异常率达到92．2％。病程在1年以内的患者H反射异常率为46．9％,而病程在10年以上者H反射异常率达到94％。其次是腓总神经运动传导速度（MCV）、腓浅神经感觉传导速度（SCV）异常率,分别是43．1％和58．8％,均超过40％。EM G结果提示：病程＜1年组拇短展肌、肱二头肌、胫前肌、趾总伸肌EM G异常率均为0,病程≥10年组异常率分别为17．6％、9．8％、21．5％、31．4％,同样随病程延长而异常率增加。结论：EM G在诊断DPN中具有较高的准确性,有利于早期发现和进行治疗。     

Motor function in diabetic neuropathy

In contrast to sensory and autonomic disturbances motor function has seldomly been studied in diabetic neuropathy. Recently quantitative studies of long-term type 1 diabetic patients have shown that the strength of the ankle and knee extensors and flexors are moderately impaired. The weakness is closely related to the severity of neuropathy. Applying quantitative electromyography the degree of reinnervation is related to the muscle strength in diabetic patients suggesting the reinnervation to be insufficient. Magnetic resonance imaging of the distal part of the leg has revealed substantial muscular atrophy closely related to the degree of muscle weakness. The present findings indicate that diabetic neuropathy often is a mixed sensory-motor neuropathy.     

Endoneurial oxygen tension and radial topography in nerve edema

Endoneurial edema occurs in numerous human and experimental neuropathies. We tested the hypothesis that the resultant increase in intercapillary distance (ICD) may result in endoneurial hypoxia. Experimental galactose neuropathy (EGN) was chosen since in this model, edema is due to the accumulation of galactitol, which does not directly damage nerve fibers, so that it was possible to study the role of endoneurial edema alone. We measured endoneurial oxygen tensions (PnO2) using oxygen-sensitive microelectrodes and related PnO2 radial topography to ICD. We also determined local oxygen consumption (VLO2) and critical PnO2(PcritO2). EGN and age-matched controls were studied at 4 months. (1) Caudal nerve conduction velocity was reduced in EGN. (2) The PnO2 values were reduced in EGN and the PnO2 histogram was shifted into the hypoxic range. These changes were paralleled by a significant increase in ICD in EGN. (3) The radial topography of PnO2 in EGN differed from the relatively uniform distribution in control nerves. In EGN the subperineurial PnO2 was significantly lower than the PnO2 at the center of the fascicle. These changes were paralleled by a significantly greater increase in ICD in the periphery. (4) That the PnO2 reduction in EGN was significant is suggested by the marked reduction in VLO2 and the large percentage (greater than 75%) of intrafascicular regions that fell below PcritO2 in EGN.     

Treatment options in painful diabetic neuropathy

Diabetic neuropathy is common in patients with diabetes mellitus, and 7.5% of diabetics experience pain from diabetic neuropathy. Complications of diabetes mellitus are more common where control of the disease is not optimal. By improving the control of the disease, both the neuropathy and the pain it can produce may be improved. The pain of diabetic neuropathy can frequently be controlled using analgesics, antidepressants, anticonvulsants, topical capsaicin, and neuromodulation, either alone or in any combination.     

糖尿病性周围神经病患者受累神经的分布特点

目的 探讨糖尿病件周围神经病(DPN)患者受累神经的分布特点.方法 对900例2型糖尿病并发DPN患者进行感觉及运动神经传导速度检测,对受累神经的分布进行分析.结果 本组感觉神经异常率为89.3%;包括65.2%(587例)的正中神经、38.9%(350例)的尺神经、89.3%(804例)的腓浅神经、60.4%(544例)的腓肠神经及29.6%(64例)的胫后神经异常.运动神经异常率为34.5%;包括32.1%(289例)的正中神经、28.7%(258例)的腓总神经、22.7%(49例)的胫神经异常.感觉神经异常率明显高于运动神经异常率(P<0.01);下肢感觉神经异常率明显高于上肢(P<0.01).结论 DPN患者受累的感觉神经以腓浅神经、正中神经、腓肠神经最普遍,受累的运动神经以正中神经、腓总神经为多见.     

Restless legs syndrome in diabetic neuropathy: a frequent manifestation of small fiber neuropathy

As the occurrence of restless legs syndrome (RLS) in diabetes is controversial, the aim of this study was to assess the prevalence of RLS in a cohort of patients with diabetic neuropathy and to analyze the features of the associated neuropathy. We investigated the occurrence of RLS diagnosed in accordance with the criteria of the International Restless Legs Syndrome Study Group in a cohort of patients with polyneuropathy and mononeuropathy multiplex associated with diabetes mellitus (DM), or impaired glucose tolerance (IGT), or impaired fasting glucose (IFG) in a retrospective study. RLS was present in 33/99 patients with neuropathy associated with DM/IGT/IFG (84 with distal polyneuropathy and 15 with multiple mononeuropathy). Comparing patients with or without RLS, small fiber sensory neuropathy was more common in the RLS patients (15/33 vs. 15/66), as were symptoms of burning feet (10/33 vs. 6/66). In several patients, RLS was responsive to neuropathic pain medications. The frequent occurrence of RLS in association with thermal dysesthesias may reflect the involvement of small sensory fibers in the form of hyperexcitable C fibers or A-delta fiber deafferentation. We suggest that RLS may be triggered by abnormal sensory inputs from small fibers, especially involved in neuropathy associated with DM/IGT/IFG. Our data show that RLS is a relevant feature of diabetic neuropathy, as a frequent and potentially treatable manifestation of small fiber involvement in the course of DM and IGT/IFG.     

Mild ischemia causes severe pathological changes in experimental diabetic nerve.

Nerve ischemia is considered one of etiological factors in the development of structural changes in peripheral nerves associated with diabetes mellitus. To assess the effect of mild ischemia on diabetic nerve, a subthreshold dose of polystyrene microspheres was injected intraarterially to occlude microvessels of the sciatic nerve and its branches in 20-week streptozotocin-induced diabetic and control rats. Diabetic sciatic and tibial nerves showed severe pathological change of myelinated fibers, whereas nondiabetic nerves were normal or had minor structural abnormalities. Morphometrical evaluation confirmed a greater frequency of abnormal myelinated fibers in diabetic nerves especially in central fascicular regions. The results indicate that diabetic nerve has an increased morphological susceptibility to nerve ischemia. Endoneurial hypoxia, which may result from hemorheological and vascular abnormalities, is likely to cause a lowered threshold to ischemic tolerance in diabetic nerve. This increased vulnerability to ischemia may render diabetic nerve unduly susceptible to hyperglycemia-induced systemic tissue abnormalities.     

Acute glucose deprivation leads to apoptosis in a cell model of acute diabetic neuropathy

OBJECTIVE: Our aims were to better understand the mechanisms underlying peripheral neuropathy with diabetes mellitus and to test the hypothesis that acute lowering of glucose levels induces apoptosis in hypoxic neurons. METHODS: We used rat dissociated dorsal root ganglion (DRG) neurons incubated in a medium high in glucose concentration (700 mg%) and room air (PO2 150 torr). After 5 days, DRG neurons were placed in hypoxic conditions (PO2 7.6 torr) with a normal-glucose (100 mg%) or high-glucose (700 mg%) medium containing 3 or 100 ng/mL of nerve growth factor. Acute lowering of glucose levels under hypoxic conditions led to apoptosis of DRG neurons. Apoptosis was demonstrated by bis-benzimide staining for nuclear fragmentation, electron microscopy, DNA laddering, and TUNEL staining. Caspase 3 immunocytochemistry and inhibition of neuronal death by the caspase inhibitor z-VAD-fmk (100 microM) confirmed that death was apoptotic. RESULTS: Hypoxia-induced death was decreased when DRG neurons were maintained in high-glucose medium, suggesting that high levels of substrate protected against hypoxia. Apoptosis was completely prevented by increasing the concentration of nerve growth factor from 3 to 100 ng/mL and was partially prevented by the addition of the antioxidant alpha-lipoic acid (500 microM). CONCLUSIONS: This model provides a novel means for studying the pathogenesis and treatment of early stages of diabetic neuropathy.     

Expression of glutamic acid decarboxylase in nervous tissue structures targeted by autoantibodies in patients with diabetic autonomic neuropathy

We have previously identified an association between symptomatic diabetic autonomic neuropathy (DAN) and autoantibodies to sympathetic and parasympathetic nervous structures. The antigens identified by these autoantibodies are not known, but glutamic acid decarboxylase (GAD) has been suggested as a candidate target, since anti-GAD autoantibodies are present in patients with long-term diabetes and GAD is expressed in a variety of cell types and structures in the nervous system. The aim of this study was to examine GAD expression in sympathetic ganglia and vagus nerve and to compare the distribution of GAD within these tissues with that of anti-sympathetic ganglia and anti-vagus nerve autoantibodies from patients with DAN, using single and double indirect immunofluorescence on tissue sections. The monoclonal antibody GAD-6, specific for GAD₆₅, gave a granular, peripheral, cytoplasmic staining pattern in sympathetic ganglion cells. Dual immunofluorescence demonstrated that serum from a patient with anti-sympathetic ganglion autoantibodies stained the same cells, but homogeneously throughout the cytoplasm. In the vagus nerve, patient's serum stained the fibres only; GAD-6 stained the cytoplasm of parasympathetic ganglion cells but only occasional fibres. In addition, GAD enzymatic activity was detectable in both sympathetic ganglia and vagus nerve. Incubation of sera or GAD-6 overnight with a crude homogenate of human brain as an antigen source abolished staining of the nervous tissues by GAD-6, but not by patients' sera. The different localisation of GAD and the autoantigens targeted by patients' sera indicates that GAD is not the target of the autoantibodies characteristic of DAN. Moreover, absorption studies using human brain homogenate suggest that the targets of anti-sympathetic ganglion and anti-vagus nerve autoantibodies are absent or represented only at low levels in the central nervous system and may be confined to the periphery.