健康皮肤标本表皮神经纤维密度研究

目的 探讨健康皮肤标本表皮神经纤维密度的参考值范围,并分析年龄、解剖部位以及种族对表皮神经分布的影响.方法 对70例皮肤标本进行皮肤神经活体组织检查.标本经10%福尔马林常规固定后切成10μm厚石蜡切片,以PGP9.5为特异性轴突标记物进行免疫组织化学染色.观察皮肤神经纤维的形态学特点,并测定表皮神经纤维密度,进行统计学分析.结果 不同年龄组小腿远端及腕部表皮神经纤维密度差异无统计学意义,但随年龄增加,各部位表皮神经分布有减少的趋势.上臂(91.8±21.1)、大腿近端(89.2±21.4)的表皮神经分布较腕部(64.5±22.5)、小腿远端(62.9±15.3)密集.健康人小腿远端的表皮神经纤维密度正常参考值范围>40.6纤维/m2.结论 通过皮肤活体组织检查技术可清晰显示神经纤维形态,便于对表皮神经纤维进行定量研究,为周围神经病的诊断和研究提供了一个可靠的平台.     

定量感觉检查对糖尿病周围神经病的早期诊断价值

目的　探讨定量感觉检查(QST)对糖尿病周围神经病的早期诊断价值。方法　对46例糖尿病 患者神经传导速度(NCV)和QST进行检测,并将其结果进行对比研究。结果　46例糖尿病患者中NCV异常 率为72.8%(35/46),NCV诊断糖尿病周围神经病32例(69.6%);QST异常率为91.3%(42/46),QST诊断 糖尿病周围神经病40例(86.9%),两者差异有显著性(P<0.05)。结论　QST较NCV对糖尿病周围神经病 变的诊断敏感性高;糖尿病患者温度觉异常率显著高于振动觉和NCV;提示其小神经纤维受损比大神经纤维 受损更常见。     

神经传导速度检测诊断酒精性周围神经病的价值

目的探讨神经传导速度(NCV)对慢性酒精中毒性周围神经病(CAPN)的诊断价值。方法采用肌电图检测52例CAPN患者的正中神经、尺神经、腓神经和胫神经的NCV,并与26例健康者进行对照比较。结果CAPN患者的NCV异常率为73.12%,明显高于对照组;下肢NCV异常率(80.77%)高于上肢异常率(76.47%);感觉神经传导速度(SCV)异常率(82.73%)高于运动神经传导速度(MCV)异常率(75.26%)。结论NCV检测可作为酒精中毒性周围神经病的方法之一。     

糖尿病周围神经病肌电图临床分析

目的：探讨糖尿病并发周围神经病的肌电图特点、诊断价值。方法：采用NDI－200型肌电诱发电位仪检测糖尿病周围神经病人50例，与35例正常人肌电图对照，统计分析。结果：观察组NCV检查260条神经异常率80％。正中神经、尺神经、腓总神经、腌肠神经全部受累，下肢比上肢重，感觉神经异常率高于运动神经。可见纤颤电位、正相波以及增大的波幅和时限。对照组NCV检查周围神经无异常。结论：NCV和EMG能敏感地评价糖尿病周围神经受损程度。     

糖尿病周围神经病肌电图临床分析

目的 :探讨糖尿病并发周围神经病的肌电图特点、诊断价值。方法 :采用NDI 2 0 0型肌电诱发电位仪检测糖尿病周围神经病人 5 0例 ,与 3 5例正常人肌电图对照 ,统计分析。结果 :观察组NCV检查 2 60条神经异常率 80 %。正中神经、尺神经、腓总神经、腓肠神经全部受累 ,下肢比上肢重 ,感觉神经异常率高于运动神经。可见纤颤电位、正相波以及增大的波幅和时限。对照组NCV检查周围神经无异常。结论 :NCV和EMG能敏感地评价糖尿病周围神经受损程度。     

Lambert-Eaton肌无力综合征45例临床及电生理回顾性分析

目的 通过对我院Lambert-Eaton肌无力综合征(Lambert-Eaton myasthenia syndrome,LEMS)患者的回顾性分析,分析此病的临床表现和伴发的神经电生理异常.方法 总结1993-2008年我院诊断的45例LEMS患者的一般情况、神经系统临床表现和体征、伴发的内科和全身疾病的情况.所有患者均进行神经电生理检测,包括神经传导速度(NCV)和重复神经电刺激(RNS).部分患者行针极肌电图和皮肤交感反射(SSR)检查.结果 (1)患者出现神经系统症状的平均年龄为(51.2±6.8)岁.最常见临床表现为双下肢无力(35例),其后依次为双上肢无力(10例)、构音障碍(3例)和颈肌无力(2例).神经系统体征中最常见为双下肢或上肢轻度力弱(40例),双下肢腱反射或跟反射减低或消失(38例)以及口干或便秘等自主神经症状(30例).(2)神经电生理检查:所有患者尺神经高频刺激递增达156% ～636%,其中29例同时出现低频递减.所有患者行NCV检查,感觉神经传导速度(SCV)异常或SCV合并运动神经传导速度异常者19例(42%).30例患者行针极肌电图检查,有异常发现者20例.25例行SSR的患者中发现13例异常.结论 LEMS最常见的临床症状为双下肢无力,其次为自主神经症状.患者除了有重复神经电刺激的异常,还伴有周围神经和肌肉的电生理异常以及自主神经系统的异常,提示临床表现可能混杂有神经或肌肉病变的原因.     

交感神经皮肤反应对糖尿病周围神经病变早期发现的应用价值

目的探索交感神经皮肤反应（SSR）检测对糖尿病周围神经病的亚临床型的诊断意义。方法对30健康对照组和80例无周围神经病症状的糖尿病患者（糖尿病组）进行SSR和NCV检测,比较健康对照组和糖尿病组的SSR值及糖尿病组的SSR和NCV的异常率,并进行统计学分析。结果糖尿病组与对照组比较,上下肢潜伏期及波幅差异均有统计学意义（P〈0.05）;糖尿病组SSR和NCV的异常率比较,SSR异常率高于NCV,差异有统计学意义（P〈0.05）。结论交感神经皮肤反应可发现糖尿病周围神经病亚临床型,是诊断早期糖尿病周围神经病的亚型临床的可靠方法 。     

慢性酒精性周围神经病的电生理改变

目的探讨慢性酒精性周围神经病的电生理特点和诊断价值.方法检测36例慢性酒精中毒患者与35例正常人肌电图对照,统计分析.结果观察组中确诊为临床或亚临床周围神经病的共30例(83.3 3%).观察组的正中神经、尺神经、胫后神经、腓总神经、腓肠、腓浅神经传导速度(NCV)及波幅明显低于正常对照组,感觉神经异常率高于运动神经,下肢异常率高于上肢.各神经传导速度与酒精摄入总量(TLDE)呈负相关.结论酒精对周围神经的毒性呈剂量依赖性.神经电生理检查能敏感地评价慢性酒精中毒患者的周围神经受损程度.     

2型糖尿病患者皮肤交感反应异常情况及其相关因素

目的探讨2型糖尿病患者皮肤交感反应(SSR)异常情况及其相关因素。方法对354例2型糖尿病患者及65名健康体检者进行SSR检测。根据SSR参考值将2型糖尿病患者分为SSR正常组和SSR异常组,比较两组的临床资料。采用Logistic回归分析2型糖尿病患者SSR异常的相关因素。结果 SSR正常组为238例(67.23%),SSR异常组为116例(32.77%)。SSR异常组中上肢异常率(16.95%)显著低于下肢异常率(27.68%)(P=0.001)。与SSR正常组比较,SSR异常组病程显著延长,神经传导速度(NCV)异常及糖尿病视网膜病变比率显著增高(均P0.01),其余各指标差异均无统计学意义。Logistic回归分析显示,视网膜病变(OR=1.588,95%CI:0.991~2.545,P=0.045)及NCV异常(OR=3.052,95%CI:1.847~5.042,P=0.000)是2型糖尿病患者SSR异常的独立相关因素。结论糖尿病患者SSR的异常率为32.77%;下肢异常率明显高于上肢。糖尿病病程越长,越容易发生SSR异常。糖尿病视网膜病变和NCV异常是2型糖尿病患者SSR异常相关的独立相关因素。     

帕金森病患者皮肤神经磷酸化α-突触核蛋白研究

目的探讨帕金森病患者磷酸化α-突触核蛋白(phosphorylated α synuclein,p-α-syn)在皮肤神经中的沉积特点,以及其作为帕金森病外周生物标志物的可能性。方法纳入2017年6月1日至2018年8月31日就诊于郑州大学第一附属医院神经内科的15例帕金森病患者及同期年龄匹配的健康志愿者31名,进行13项小纤维神经病和症状问卷(SFN-SIQ)评分。将帕金森病患者按照主要临床表现分为运动迟缓(n=7)和静止性震颤(n=8)2个亚组,并以Hoehn-Yahr分级评价病情的严重程度,其中0~2.5级为早期组(n=11),3.0~5.0级为中晚期(n=4)。采用环形钻孔器取帕金森病患者小腿和颈部皮肤,健康对照组只取小腿部位皮肤,进行免疫组织化学和免疫荧光染色,观察p-α-syn在皮肤神经中的沉积情况并计数穿过单位长度基底膜的神经纤维数量即表皮内神经纤维密度(intraepidermal nerve fiber density,IENFD)。结果12/15的帕金森病患者表皮下神经丛、真皮神经束、汗腺、立毛肌、血管或毛囊周围神经中可见点状或线状p-α-syn沉积,健康对照组皮肤中未见沉积。p-α-syn在单个部位沉积的阳性率分别为小腿6/15、颈部7/15,总阳性率为12/15。帕金森病组的IENFD为(6.85±1.94)根/mm,较对照组[(10.45±3.70)根/mm]明显下降(t=-3.303,P=0.002),与SFN-SIQ评分呈负相关(r=-0.561,P=0.046)。疾病早期与中晚期患者之间,以及以震颤和以运动迟缓为主要表现的患者之间比较,p-α-syn沉积阳性率和IENFD差异均无统计学意义。结论p-α-syn在帕金森病患者皮肤神经纤维中沉积,伴随IENFD明显下降。提示皮肤神经中p-α-syn沉积可能是帕金森病固有的外周病理改变,有作为帕金森病患者诊断外周生物标志物的可行性。     

Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies

OBJECTIVE: To study intraepidermal nerve fiber (IENF) density in distal leg skin biopsies, sural nerve morphometry, electrophysiology, and clinical features in patients with peripheral neuropathies. METHODS: We studied 26 patients with neuropathic complaints who had undergone clinical evaluation, nerve conduction studies, distal leg skin biopsy, and sural nerve biopsy. We quantified densities of IENF and of myelinated and unmyelinated fibers in the sural nerve. Associations among skin and sural nerve morphometric measures and sensory nerve action potential (SNAP) amplitudes were examined nonparametrically. Morphometric measures were examined with respect to diagnostic category of neuropathy. RESULTS: IENF density correlated with the densities of sural nerve total myelinated (r = 0.57, p = 0.0011), small myelinated (r = 0.53, p = 0.0029), and large myelinated fibers (r = 0.49, p = 0.0054). There was a trend toward an association between IENF and sural nerve unmyelinated fiber densities (r = 0.32, p = 0.054). Sural SNAP amplitude and large myelinated fiber densities were highly correlated (r = 0.87, p < 0.0001). IENF density and sural nerve small fiber measures were concordant in 73% of patients. Reduced IENF density was the only indicator of small fiber depletion in 23% of cases. It was usually normal in acquired demyelinating neuropathies and where clinical suspicion for neuropathy was low. CONCLUSIONS: Distal leg Intraepidermal nerve (IENF) density may be more sensitive than sural nerve biopsy in identifying small fiber sensory neuropathies. Assessments of IENF density and large fiber measures on biopsy and electrophysiology are both useful for characterizing sensory and sensorimotor neuropathies.     

Diagnostic validity of epidermal nerve fiber densities in painful sensory neuropathies

In this prospective study, intraepidermal nerve fiber densities (IENFD) and subepidermal nerve plexus densities (SENPD) were quantified by immunostaining in skin punch biopsies from the distal calf in 99 patients with clinical symptoms of painful sensory neuropathy and from 37 age-matched healthy volunteers. The clinical diagnosis was based on history and abnormal thermal thresholds on quantitative sensory testing (QST). In patients with neuropathy, IENFD and SENPD were reduced to about 50% of controls. Elevated warm detection thresholds on QST correlated with IENFD but not with SENPD. Using receiver-operating characteristic (ROC) curve analysis of IENFD values, the diagnostic sensitivity for detecting neuropathy was 0.80 and the specificity 0.82. For SENPD, sensitivity was 0.81 and specificity 0.88. With ROC analysis of both IENFD and SENPD together, the diagnostic sensitivity was further improved to 0.92. The combined examination of IENFD and SENPD is a highly sensitive and specific diagnostic tool in patients suspected to suffer from painful sensory neuropathies but with normal values on clinical neurophysiological studies.     

Quantitative pathology of cutaneous nerve terminal degeneration in the human skin

Pathological diagnosis of neuropathy has traditionally depended on ultrastructural examinations of nerve biopsy specimens, particularly for sensory neuropathies affecting unmyelinated and small-myelinated nociceptive nerves. These sensory nerves terminate in the epidermis of the skin, and the pathology of neuropathy usually begins from nerve terminals. We investigated the feasibility of diagnosing small-fiber sensory neuropathy by evaluating cutaneous innervation. Skin biopsy specimens of 3-mm in diameter were obtained from the distal leg and the distal forearm of 55 healthy controls and 35 patients with sensory neuropathy. In the healthy controls, conventional intraepidermal nerve fiber densities (IENF densities) as measured using the image analysis system in the distal forearm and in the distal leg were correlated (r=0.55, P<0.0001), with significantly higher values in the distal forearm than in the distal leg (17.07+/-6.51 vs 12.92+/-5.33 fibers/mm, P<0.001). Compared to IENF densities of healthy controls, these values of neuropathic patients were significantly reduced in the distal forearm (5.82+/-6.50 fibers/mm, P<0.01) and in the distal leg (2.40+/-2.30, P<0.001). We further explored the possibility of quantifying skin innervation by counting "ocular intraepidermal nerve fiber density" (ocular nerve fiber density) with no aid of an image analysis system. This was based on the fact that the epidermal length on specifically defined sections was very close to the predicted epidermal length of 3 mm, the diameter of skin punches (P=0.14). Ocular nerve fiber densities were significantly correlated with IENF densities as measured by the image analysis system (r=0.99, P<0.0001). Dermal nerve fibers of neuropathic patients either disappeared or became degenerated. These findings were consistent with the notion of early terminal degeneration in neuropathy, and will facilitate quantitative interpretation of epidermal innervation in human neuropathy.     

Skin biopsy in assessing meralgia paresthetica

Introduction: Meralgia paresthetica is a focal neuropathy caused by compression of the lateral femoral cutaneous nerve (LFCN). The disease can be difficult to assess by neurophysiological or imaging studies. Methods: We studied 5 patients who presented to our neuromuscular clinic from April 2012 to December 2014 with a clinical suspicion of meralgia paresthetica and had skin biopsies with intraepidermal nerve fiber density (IENFD) evaluation. Results: The mean age at onset was 37.2 (range 21–59) years. There were 4 women and 1 man. Two were obese, 2 wore tight jeans, and 1 had mild diabetes mellitus. IENFD was reduced in the symptomatic proximal thigh in all 5 patients and was also reduced in the asymptomatic thigh in 2 patients. It was normal in the distal leg in 4 patients. Conclusion: Meralgia paresthetica is associated with loss of small intraepidermal nerve fibers. Skin biopsy with IENFD evaluation may be a useful diagnostic tool for this disease. Muscle Nerve 53 : 641–643, 2016     

Small‐nerve‐fiber pathology in critical illness documented by serial skin biopsies

Introduction: Small‐fiber pathology can develop in the acute phase of critical illness and may explain chronic sensory impairment and pain in critical care survivors. Methods: Eleven adult ischemic stroke patients in a neurocritical care unit were enrolled in an observational cohort study. Intraepidermal nerve fiber density (IENFD) in the distal leg was assessed on admission to the intensive care unit and 10–14 days later, together with electrophysiological testing. Results: Of the 11 patients recruited, 9 (82%) had sepsis or multiple‐organ failure. Median IENFD on admission (5.05 fibers/mm) decreased significantly to 2.18 fibers/mm (P < 0.001), and abnormal IENFD was found in 6 patients (54.5%). Electrodiagnostic signs of large‐fiber neuropathy and/or myopathy were found in 6 patients (54.5%), and autonomic dysfunction was found in 2 patients (18.2%). Conclusion: Serial IENFD measurements confirmed the development of small‐fiber sensory involvement in the acute phase of critical illness. Muscle Nerve 52 : 28–33, 2015     

Intraepidermal nerve fiber density of healthy human

Abstract

Objectives:

To analyze intraepidermal nerve fiber density (IEFND) by skin biopsy, evaluate the effect of age, anatomical sites, and ethnic origin on IEFND and develop a reference range of IENFD at the distal leg of healthy human.

Methods:

Seventy skin biopsy specimens from surgical procedures involving 70 patients were analyzed. Specimens were fixed routinely in formalin and thereafter embedded in paraffin. Nerve fibers of 10-μm-thick sections were observed using immunoperoxidase staining with panaxonal antibody protein gene product 9·5 (PGP 9·5). The morphology of intraepidermal nerve fibers (IENFs) and the IENFD was determined using light microscope. The statistical analysis was performed with SPSS 16·0 software.

Results:

No significant correlation was observed between IENFD and age (P_wrist = 0·830, P_{distal leg} = 0·478). The significant correlation was observed between IENFD and anatomic site (P = 0·001), the IENFD of upper arm and proximal thigh were significantly higher than that of wrist and distal leg. The reference range for IENFD of distal leg in normal Chinese humans was 40·55 fibers/mm². The IEFND of Chinese healthy human was significantly lower than that of Finnish (62·87 ± 15·25 vs 114·617 ± 32·322 fibers/mm², P < 0·05).

Discussion:

Skin biopsy may be a useful tool in sensory neuropathies. IENFD is independent of age, but varies in different parts of the body. The proximal sites have a higher IENFD, but no significant difference is found between the wrist and distal leg.     

Neuropathic symptoms and findings in women with Fabry disease

ObjectiveTo examine the neurologic and neurophysiologic findings and neurologic symptoms in 12 women with Fabry disease and to study the relationship between the subjective symptoms and the findings on the various tests done.MethodsNeurography, vibratory and thermal quantitative sensory testing (QST), skin biopsy for measuring intraepidermal nerve fiber density (IENFD). Heart rate variability (HRV) and sympathetic skin response (SSR) tests for detecting autonomic dysfunction, pain-, depression- and somatic symptom questionnaires and clinical examination.ResultsOnly two women had no persistent symptoms or signs of polyneuropathy, 10 had symptoms of small fiber neuropathy. Neurological examination was normal in most patients. Five patients had decreased IENFD or thermal hypoesthesia in QST. In QST, Aδ-fiber function for innocuous cold was more often impaired than C-fiber function. Conventional nerve conduction studies were mostly normal. Carpal tunnel syndrome (CTS) incidence was increased, 25% had symptomatic CTS.ConclusionsHeterozygous women carrying the gene for Fabry disease have symptoms and findings of small-fiber polyneuropathy more often than has previously been considered. The prevalence of CTS is also increased.SignificanceWhile the clinical diagnosis of small-fiber neuropathy is difficult, the diagnostic yield can be increased using a combination of thermal QST and IENFD measurements.     

Small fibers in Fabry disease: baseline and follow-up data under enzyme replacement therapy

Fabry disease (FD) is an X-linked lysosomal storage disorder which may lead to impaired peripheral nerve function, mostly affecting small nerve fibers, and to neuropathic pain. Characteristics of the neuropathy associated with FD and the covariates for its development and temporal course have not been described in a large cohort. We studied small fiber function and morphology in 120 Fabry patients at baseline and in subgroups of these until 4-year follow-up. Baseline neurological (89/120) and electrophysiological (106/120) examination was mostly normal. Quantitative sensory testing revealed impaired cold detection thresholds in 84% of men and 39% of women. Lower leg intraepidermal nerve fiber density (IENFD) was reduced to 46% in Fabry patients compared to controls and to 12.5% in men with impaired renal function. Patients with abnormal IENFD more often had pain. Group means for IENFD did not improve under enzyme replacement therapy (ERT), but IENFD in the back increased under ERT in 4/15 patients with good renal function and clinical improvement. Cutaneous cytokine gene expression did not differ from controls. We conclude that ERT may improve proximal skin innervation in patients with good renal function, but does not protect small fiber function in men with impaired renal function.