外国文献的中英文对照版

diabetes neuropathies: update on definitions,diagnostic criteria,estimation of severity,and treatments

糖尿病神经病变：更新的定义，诊断标准，估计的严重程度，与治疗

Tesfaye S,Boulton A J.Dyck P J,et al.

内容概要，博尔顿一·戴克磷，等。

Abstract

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13–18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

前联席会议第十九年糖尿病神经病变研究组欧洲糖尿病研究协会（neurodiab）和第八届国

际糖尿病神经病变在多伦多，加拿大，–13 18 2009年十月，专家小组召开了提供更新的定义，分类，诊断标准，治疗糖尿病周围神经病变（标准草案），自主神经病变，痛苦的标准草案，和结构改变的标准草案。

CLASSIFICATION AND DEFINITION OF DIABETIC NEUROPATHIES

定义和分类糖尿病神经病变

Solomon Tesfaye, MD, FRCP,1 Andrew J.M. Boulton, MD,2 Peter J. Dyck, MD,3 Roy Freeman, MD,4 Michael Horowitz, MD, PHD,5 Peter Kempler, MD, PHD,6 Giuseppe Lauria, MD,7 Rayaz A. Malik, MD,2 Vincenza Spallone, MD, PHD,8 Aaron Vinik, MD, PHD,9 Luciano Bernardi, MD,10 Paul Valensi, MD,11 and on behalf of the Toronto Diabetic Neuropathy Expert Group*

所罗门内容概要，医学博士，联邦民事诉讼规则，1安得烈J .博尔顿，医学博士，2彼得·戴克，医学博士，医学博士，4 3罗伊，迈克尔霍洛维茨，医学博士，博士，5彼得肯普勒，医学博士，博士，6家7 rayaz朱塞佩，医学博士，马利克，医学博士，医学博士，博士2文森泽斯帕龙，，8亚伦vinik，医学博士，博士，9大卢西亚诺，医学博士，10保罗瓦朗西，博士，11代表多伦多糖尿病神经病变专家组

CLASSIFICATION AND DEFINITION OF DIABETIC NEUROPATHIES

The neuropathies developing in patients with diabetes are known to be heterogenous by their symptoms, pattern of neurologic involvement, course, risk covariates, pathologic alterations, and underlying mechanisms (1,2). Thomas (3) and Boulton et al. (4) separated these into generalized and focal/multifocal varieties (e.g., multiple mononeuropathy, lumbosacral, thoracic, and cervical radiculoplexus neuropathies) (3,4). It is known that similar patterns of neuropathy occur in patients without diabetes

(2). Moreover, diabetic patients can develop chronic inflammatory demyelinating polyradiculopathy.

The evidence that generalized varieties can be further classified into at least two major subgroups seems compelling (3,4). The typical DPN is a chronic, symmetrical, length-dependent sensorimotor polyneuropathy (DSPN) and is thought to be the most common variety (1). It develops on (or with) a background of long-standing hyperglycemia, associated metabolic derangements (increased polyol flux, accumulation of advanced glycation end products, oxidative stress, and lipid alterations among other metabolic abnormalities) and cardiovascular risk factors (5–7). Alterations of microvessels, similar to those observed in diabetic retinopathy and nephropathy, appear to be associated with the pathologic alterations of nerves (8). Total hyperglycemic exposure is perhaps the most important risk covariate (5,7). This variety has been shown to be stabilized, perhaps even improved, by rigorous glycemic control. This polyneuropathy has been shown to be statistically associated with retinopathy and nephropathy (1,6). Autonomic dysfunction and neuropathic pain may develop over time.

The atypical DPNs are different from DSPN in several important features, i.e., onset, course, manifestations, associations, and perhaps putative mechanisms (3,4,9). They appear to be intercurrent varieties, developing at any time during the course of a patient's diabetes (3,9). Onset of symptoms may be acute, subacute, or chronic, but the course is usually monophasic or fluctuating over time. Pain and autonomic symptoms are typical features (3,9) and altered immunity has been suggested. Studies have suggested that impaired fasting glucose or impaired glucose tolerance (IGT) is more common in chronic idiopathic axonal polyneuropathy, but other studies do not support this view (3,10).

定义和分类糖尿病神经病变的发展neuropathiesthe糖尿病患者已知是异质性的症状，模式的神经系统的参与，当然，风险变量，病理改变，和基本机制（1 , 2）。托马斯（3）和博尔顿等。（4）分隔成广义和联络/多品种（例如，多慢性神经痛，腰骶神经根神经病变及颈，胸，）（3 , 4）。据了解，类似的模式，神经病变发生在糖尿病患者（2）。此外，糖尿病患者可发展为慢性炎症性脱髓鞘性多发性神经病。

有证据表明，广义的品种可进一步分为至少2个主要分组似乎令人信服的（3 , 4）。典型的病变是一种慢性，对称，长度依赖性神经病感觉（dspn）和被认为是最常见的种类（1）。它的发展对（或）在长期的高血糖，代谢紊乱（增加醇通量，积累的先进的糖化终产物，氧化应激，和血脂的变化之间的其他代谢异常）和心血管危险因素（5–7）。改建的微血管，类似的观察，糖尿病视网膜病变和肾病，似乎与病理改变神经（8）。总高血糖曝光，也许是最重要的风险变量（5 , 7）。该品种已被证明是稳定的，甚至可能提高，严格的血糖控制。这神经病已

被证明是统计学与视网膜病变和肾病（1 , 6）。自主神经功能障碍和神经性疼痛可能随着时间的发展。

非典型标准草案是不同的dspn在几个重要的特点，即，发病，当然，表现，协会，和也许假定机制（3,4,9）。他们似乎是并发品种，发展在任何时间的过程

中病人的糖尿病（9）。出现症状，可能是急性，亚急性或慢性，但，当然通常是单相或波动随着时间的。疼痛和植物神经症状的典型特征（9）和免疫功能的改变已建议。研究表明，空腹血糖或糖耐量受损（公司）是较常见的慢性特发性轴索神经病，但其它的研究不支持这一观点（3 , 10）。

Diabetic sensorimotor polyneuropathy

Case definition.

The 1988 San Antonio Conference on Diabetic Neuropathy (11), Boulton et al. (4), and the American Academy of Neurology (AAN), American Association of Electrodiagnostic Medicine (AAEM), and American Academy of Physical Medicine and Rehabilitation (AAPM&R) (12) have proposed criteria for diabetic neuropathies.

We propose separate definitions for typical DPN (DSPN) and atypical DPNs. DSPN is a symmetrical, length-dependent sensorimotor polyneuropathy attributableto metabolic and microvessel alterations as a result of chronic hyperglycemia exposure (diabetes) and cardiovascular risk covariates. An abnormality of nerve conduction tests, which is frequently subclinical, appears to be the first objective quantitative indication of the condition. The occurrences of diabetic retinopathy and nephropathy in a given patient strengthen the case that the polyneuropathy is attributable to diabetes. Other causes of sensorimotor polyneuropathy need to be excluded. For epidemiologic surveys or controlled clinical trials of DSPN, we advocate the use of nerve conduction (NC) testing as an early and reliable indicator of the occurrence of this neuropathy. To be reliable the test must be done rigorously using appropriate reference values corrected for applicable variables. Volunteered or elicited symptoms and signs and other clinical neurophysiologic abnormalities are also needed to characterize the symptoms, signs, and overall severity of the polyneuropathy. Recent studies emphasize the importance of the proficiency of the clinical neurologic assessment (13,14). Atypical DPNs have been less well characterized and studied.

Estimating severity.

Estimating the severity of DSPN has not received the attention it deserves. For a given patient with diabetes, it is not sufficient to simply identify

patients as having or not having DSPN—severity also needs to be ascertained. We suggest a reliable objective and quantitative measure (i.e., NC abnormality) as the minimal criteria for the diagnosis of DSPN. When NC values have not been assessed, it is not possible to provide a confirmed diagnosis of DSPN—only a possible or probable diagnosis. Since the severity of DSPN is a combination of neuropathy symptoms, signs, neurophysiologic test abnormalities, and other dysfunctions and impairments, the sum scores of various measures of neurologic signs, symptoms, neurophysiologic test abnormalities, or scores of function of activities of daily living may provide an indication of the severity (13).

An alternative approach to estimating severity is to indicate severity by grades. Dyck (15) described the stages of severity:

?Grade 0 =no abnormality of NC, e.g., Σ 5 NC normal deviates <95th percentile or another suitable NC criterion

?Grade 1a = abnormality of NC, e.g., Σ 5 NC normal deviates ≥95th percentile without symptoms or signs

?Grade 1b =NC abnormality of stage 1a plus neurologic signs typical of DSPN but without neuropathy symptoms

?Grade 2a = NC abnormality of stage 1a with or without signs (but if present, <2b) and with typical neuropathic symptoms ?Grade 2b =NC abnormality of stage 1a, a moderate degree of weakness

(i.e., 50%) of ankle dorsiflexion with or without neuropathy

symptoms.

糖尿病感觉神经病

病例定义。1988圣安东尼奥会议对糖尿病神经病变（11），博尔顿等人。（4），和美国神经病学会（公告），肌电美国医学协会（软件），和美国科学院物理医学与康复（包括研发）（12）提出的标准治疗糖尿病周围神经病变。

我们提出不同的定义的典型病变（dspn）和非典型标准草案。dspn是对称的，长度依赖性神经病感觉标志着代谢和微血管改建由于慢性高血糖（糖尿病）和心血管风险暴露变量。一个异常的神经传导测试，这往往是亚，似乎是第一次客观的定量指标条件。糖尿病视网膜病变和肾病的发生在一个给定的病人加强的情况，原因是糖尿病性多发性神经病。其他原因的感觉神经病需要排除。流行病学调查或控制的临床试验dspn，我们提倡使用神经传导（数控）测试作为一个可靠的早期指标发生这种病变。是可靠的测试必须做到严格使用适当的参考值纠正适用变量。自愿或引起的症状和体征与其他临床神经生理异常也需要描述的症状，体征，和整体的严重性神经病。最近的研究强调的重要性，熟练的临床神经功能评价（13 , 14）。非典型标准草案已不太好的特点和研究。

估计严重性。估计的严重dspn却没有得到应有的重视。对于一个给定的糖尿病患者，这是不足以完全确定患者有或没有dspn-severity还需要确定。我们提出

一个可靠的客观和定量测量（即，数控异常）的最低限度标准的诊断dspn。当

数控价值观没有得到评估，这是不可能提供一个确诊的dspn-only可能或可能的诊断。由于严重的dspn是结合神经病变症状，体征，神经生理测试异常，和其他功能紊乱和障碍，总结成绩的各种措施的神经系统的迹象，症状，神经生理测试异常，或分数功能的日常生活活动可能提供一个指标的严重性（13）。

另一种方法来估计的严重性是表明严重性等级。戴克（15）描述阶段的严重性：

0级=没有异常，例如，Σ5数控正常偏离<第九十五位数或其他合适的数控标准

一级A =异常，例如，Σ5数控正常偏离≥第九十五位数没有症状或体征

1 B级=数控异常期加神经症状典型的dspn但没有神经病症状

等级2 =数控异常期或无症状（但如果存在，<乙）和典型的神经症状

等级乙=数控异常期，中等程度的弱点（即，50%）踝关节背屈或无神经症状。Definitions of minimal criteria for typical DPN

1. Possible DSPN.

The presence of symptoms or signs of DSPN may include the following: symptoms–decreased sensation, positive neuropathic sensory symptoms (e.g., “asleep numbness,” prickling or stabbing, burning or aching pain) predominantly in the toes, feet, or legs; or signs–symmetric decrease of distal sensation or unequivocally decreased or absent ankle reflexes.

2. Probable DSPN.

The presence of a combination of symptoms and signs of neuropathy include any two or more of the following: neuropathic symptoms, decreased distal sensation, or unequivocally decreased or absent ankle reflexes.

3. Confirmed DSPN.

The presence of an abnormality of NC and a symptom or symptoms or a sign or signs of neuropathy confirm DSPN. If NC is normal, a validated measure of small fiber neuropathy (SFN) (with class 1 evidence) may be used.

To assess for the severity of DSPN, several approaches can be recommended: the graded approach outlined above, various continuous measures of sum scores of neurologic signs, symptoms or nerve test scores, scores of function of acts of daily living or of predetermined tasks or of disability.

Irrespective of which approach is used, it is necessary to ensure good performance of evaluations with monitoring proficiency.

4. Subclinical DSPN.

The presence of no signs or symptoms of neuropathy are confirmed with abnormal NCs or a validated measure of SFN (with class 1 evidence).

We recommend that definitions 1, 2, or 3 be used for clinical practice and definitions 3 or 4 be used for research studies.

Atypical DPNs

Before further classification of these polyneuropathies, setting the minimal criteria for diagnosis and estimating severity and further characterizing of epidemiologic and mechanistic studies are needed. The issue of painful, autonomic, and nerve morphologic abnormalities are discussed in subsequent sections.

定义的最低标准，典型病变

1。可能dspn。在场的症状或体征dspn可包括以下内容：症状–下降的感觉，积极的感觉症状（例如，“沉睡麻木刺痛，”或刺痛，燃烧或酸痛）主要在脚趾，脚，或腿；或标志–对称减少远端感觉或明确的减少或缺乏踝反射。

2。可能dspn。存在一个结合症状和体征病变包括2个或更多下列：神经症状，降低远端感觉，或明确的减少或缺乏踝反射。

3。确认dspn。一个异常的存在和数控的症状或症状或体征或症状神经病证实dspn。如果是正常的，一个经审定的措施，小纤维神经病（单频网）（1级证据）可以使用。

评估的严重性，dspn，有几个方法可以建议：分级上述方法，各种措施的连续得分总和的神经系统的迹象，症状或神经考试分数，分数的日常生活行为或预定任务或残疾。不论哪种方法是使用，这是必要的，以确保良好的性能评价与监测能力。

4。亚dspn。在场的没有迹象或症状神经病证实异常新生或验证措施的单频网（1级证据）。

我们建议的定义，1，2，或3用于临床实践和定义3个或4个用于研究研究。

非典型标准草案

在进一步分类这些神经病，设定的最低标准的诊断和估计的严重性和进一步描述流行病学和机理研究是必要的。这个问题的痛苦，自主，和神经形态学异常的讨论在随后的章节。

PAINFUL DPN

A definition of peripheral neuropathic pain (NP) in diabetes, adapted from a definition recently proposed by the International Association for the Study of Pain (16), is “pain arising as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes.” The prevalence of NP in the diabetic population is difficult to estimate as definitions have varied enormously among studies; however, it is crudely estimated that between 3 and 25% of patients might experience NP (17). Similarly, there are limited data on the natural history of painful DPN with some studies suggesting that painful symptoms improve with the worsening of the sensory loss and others reporting no appreciable occurrence of remissions (17).

In practice, the diagnosis of painful DPN is a clinical one, which relies on the patient's description of pain. The symptoms are distal, symmetrical, often associated with nocturnal exacerbations, and commonly described as prickling, deep aching, sharp, like an electric shock, and burning (13) with hyperalgesia and frequently allodynia upon examination (17). The symptoms are usually associated with the clinical signs of peripheral neuropathy, although occasionally in acute painful DPN, the symptoms may occur in the absence of signs. A number of simple numeric rating scales can be used to assess the frequency and severity of painful symptoms (18), and other causes of NP must be excluded. The severity of pain can be reliably assessed by the visual analog scale, which is the oldest and best validated measure, or the numerical rating scale, e.g., the 11-point Likert scale (0 = no pain, 10 = worst possible pain), which has been most widely used in neuropathic pain studies. A number of validated scales and questionnaires including the Neuropathic Pain Symptoms Inventory, Brief Pain Inventory, Neuropathic Pain Questionnaire, and McGill Pain Questionnaire, may be used (18). Quality of life (QoL) improvement should also be assessed, preferably using a validated neuropathy-specific scale such as NeuroQol or the Norfolk Quality of Life Scale (19). Outcomes must be measured using patient-reported improvement in scales for pain and QoL as measured on validated instruments. External observers can play no part in the assessment of the subjects' responses to new therapies for NP; thus, measures such as the “physician's global impression of response” are not valid.

For clinical trials of putative new therapies for painful DPN, rigorous patient selection with the use of NP scales and outcome measures are indicated. Inclusion criteria for such trials would normally include NP associated with DPN for >6 months duration, mean weekly pain score of between 4 and 10 on an 11-point numerical rating scale, exclusion of pain not associated with DPN, mononeuropathies or proximal neuropathies, non-neuropathic chronic pain, and central pain.

Pharmacological management of painful DPN almost exclusively consists of symptomatic therapies (those that improve symptoms of painful DPN without an effect on underlying causes or natural history) (20). The antioxidant α-lipoic acid administered intravenously is the only pathogenetic treatment that has efficacy confirmed from several randomized controlled trials and confirmation in a meta-analysis (level A evidence [12]) (21). Although spinal cord stimulation might be useful in refractory painful DPN (22), insufficient evidence exists for any nonpharmacological therapies.

Level A evidence exists to support the use of tricyclic antidepressants (e.g., amitriptyline), the anticonvulsants gabapentin and pregabalin, and the serotonin and norepinephrine reuptake inhibitor duloxetine (20,23–26). There is also randomized controlled trial (RCT) evidence for the use of opiates such as oxycodone and tramadol in painful DPN (20,23). There is no evidence available to support the use of the cannabinoids (27). Preliminary evidence shows promise for topical treatment using a 5% lignocaine plaster applied to the most painful area (28), although larger RCTs are required. First-line therapies for painful DPN are a tricyclic antidepressant, duloxetine, pregabalin, or gabapentin, taking into account patient comorbidities and cost (20,23). Combinations of first-line therapies may be considered if there is pain, despite a change in first-line monotherapy (20,23). If pain is still inadequately controlled, opiods such as tramadol and oxycodone may be added in a combination treatment (20,23). A number of areas relating to painful DPN warrant further investigation including population-based prevalence and natural history studies, trials using active comparators rather than placebo, assessment of combination therapies in addition to placebo, and longer-term studies of the efficacy and durability of treatments of painful 痛苦的dpna定义周围神经性疼痛（国民党）在糖尿病，改编自一个定义最近提出的国际研究协会疼痛（16），是“痛苦而引起的直接后果异常在周围神经系统的糖尿病患者。”流行的微粒在糖尿病人口是困难的估计定义差别极大的研究；然而，这是粗略估计有3至25%的患者可能会经历党（17）。同样，有数据有限的自然历史的痛苦糖尿病周围神经病变的一些研究表明，疼痛症状的改善与恶化的感觉丧失和其他报告没有明显的发生，缓解（17）。

在实践中，诊断痛苦的病变是临床之一，它依赖于病人的痛苦的描述。症状远端，对称，往往与夜间加重，和通常称为刺痛，深痛，尖锐，像是触电，和（13）痛觉和痛（17）经常检查。症状通常与临床症状的周围神经病，虽然偶尔在急性痛苦的病变，症状可能发生在缺乏症状。一个简单的数字评定量表可用于评估的频率和严重程度的疼痛症状（18），和其他原因必须被排除的国民党。严重的疼痛可以可靠地评估的视觉模拟规模，这是最古老和最有效的措施，或数值评

定量表，例如，11点利克特量表（0 =没有疼痛，10 =最严重的疼痛），它已被广泛应用在神经性疼痛的研究。一些验证表和问卷包括神经性疼痛症状量表，简明疼痛，神经性疼痛问卷，麦吉尔疼痛问卷，可用于（18）。生活质量（生活质量）的改善也应进行评估，最好使用一个经审定的neuropathy-specific等规模neuroqol或诺福克生活质量量表（19）。结果必须是衡量使用病人报告改善表疼痛和生活质量作为衡量验证工具。外部观察员可以不参与评估受试者的反应，新的治疗方案；因此，措施，如“医生的总体印象的反应”是不正确的。

临床试验的假定新的治疗痛苦的病变，严格的病人的选择与使用微粒尺度测量结果表明。纳入标准的试验通常包括国民党与病变> 6个月时间，平均每周疼痛分数之间的4和10的11点数值评定量表，排除痛苦不与病变，mononeuropathies 或近端神经病变，非神经性慢性疼痛，和中枢性疼痛。

药理管理痛苦的病变几乎完全由对症疗法（那些改善症状，痛苦的病变没有影响的根本原因或自然史）（20）。抗氧化α-硫辛酸静脉注射是唯一的治疗，疗效证实发病从几个随机对照试验和确认在Meta分析（一级的证据[ 12 ]）（21）。虽然脊髓刺激可能是有用的难治痛苦的病变（22），证据不足，存在的任何非药物疗法。

水平的证据支持使用三环抗抑郁药（例如，阿米替林），抗癫痫药加巴喷丁和普瑞巴林，和羟色胺和去甲肾上腺素再摄取抑制剂度洛西汀（20,23–26）。也有随机对照试验（随机对照试验）的证据使用阿片类药物羟考酮和曲马多在痛苦的糖尿病周围神经病变（20,23）。没有任何证据可以支持使用大麻（27）。初步证据表明承诺用于局部治疗用5%利多卡因石膏应用于最痛苦的地区（28），虽然较大的随机对照试验需要。第一线治疗痛苦的病变是三环抗抑郁药，度洛西汀，普瑞巴林，或加巴喷丁，同时考虑到病人的合并症和成本（20,23）。组合的第一线疗法可能被视为如果有疼痛，尽管改变第一线（20,23）。如果疼痛仍然不足控制，opiods如曲马多和羟考酮可以添加在结合治疗（20,23）。多个领域涉及痛苦的病变需要进一步调查包括人口为基础的流行和自然历史研究，试验采用比较活跃，而不是安慰剂，评估结合疗法除了安慰剂，和长期研究的有效性和耐久性的治疗痛苦的神经病变（23）。

DIABETIC AUTONOMIC NEUROPATHY

Diabetic autonomic neuropathy (DAN) is a disorder of the autonomic nervous system in the setting of diabetes or metabolic derangements of

pre-diabetes after the exclusion of other causes. DAN may affect cardiovascular, gastrointestinal (GI), and urogenital systems, and sudomotor function. It may result in signs and symptoms or may be subclinically detectable by specific tests.

糖尿病自主neuropathydiabetic自主神经病变（丹）是一种疾病的自主神经系统在设定的糖尿病或代谢紊乱的糖尿病前期，在排除其他原因。丹可能影响心血管，

胃肠道（地理标志），以及泌尿生殖系统，与功能。它可能会导致症状和体征或可能是临床症状检测特定的测试。

Cardiovascular autonomic neuropathy

Epidemiology.

Cardiovascular autonomic neuropathy (CAN) is defined as the impairment of autonomic control of the cardiovascular system. The prevalence of CAN varies widely from 2.5 to 50%. Factors that influence the prevalence of CAN include the diagnostic criteria used, patient age, and the duration of diabetes (29,30). Additional clinical correlates and predictors of CAN include glycemic control, presence of DPN, nephropathy and retinopathy, blood pressure (BP) levels, obesity, smoking, and cholesterol and triglycerides levels (30,31). Intervention studies have documented the protective effect of glycemic control in type 1 diabetes (32) and a multifactorial strategy aimed at lifestyle change with pharmacological correction of hyperglycemia, hypertension, dyslipidemia, and microalbuminuria (33).

CAN is significantly associated with overall mortality (34) and in some—but not all—studies with morbidity such as silent myocardial ischemia, coronary artery disease, stroke, diabetic nephropathy progression, and perioperative morbidity. Some pathogenetic mechanisms may link CAN to cardiovascular dysfunction and diabetic complications (34). Thus, CAN assessment may be used for cardiovascular risk stratification in patients with and without established cardiovascular disease; as a marker for patients requiring more intensive monitoring during the perioperative period and other physiological stresses; and as an indicator for more intensive pharmacotherapeutic and lifestyle management of comorbid conditions.

心血管自主神经病变

流行病学。心血管自主神经病变（能）是指损害自主控制心血管系统。流行的变化从2.5到50%。影响因素的流行可以包括使用的诊断标准，病人的年龄，和糖尿病病程（仿真）。更多的临床相关性和预测可以包括血糖控制，存在糖尿病，肾病和视网膜病变，血压（血压）水平，肥胖，吸烟，和胆固醇和甘油三酯的水平（30、31）。干预的研究已经证明了保护作用的血糖控制在1型糖尿病（32）和多战略旨在改变生活方式和药物纠正高血糖，高血压，血脂异常，蛋白尿（33）。

可以是显着相关的总死亡率（34）和一些不all-studies与发病率为无症状性心肌缺血，冠状动脉疾病，中风，糖尿病肾病的进展，围手术期和发病率。一些发病机制可能链接到心血管功能障碍和糖尿病并发症（34）。因此，可以评估可

用于心血管危险分层患者和心血管疾病；作为标记患者需要更密集的监测在围手术期和其他生理应力；和作为一个指标更密集的药物治疗和生活方式管理共条件。

CAN assessment.

Cardiovascular reflex tests are the gold standard in clinical autonomic testing. These tests have good sensitivity, specificity, and reproducibility and are noninvasive, safe, well-standardized, and easily performed (35). However, a Valsalva maneuver must not be performed in patients with proliferative retinopathy. The most widely used tests assessing cardiac parasympathetic function are based on the time-domain heart rate (HR) response to deep breathing, a Valsalva maneuver, and postural change. Of these tests, HR to deep breathing has the greatest specificity (~80%). Cardiovascular sympathetic function is assessed by measuring the BP response to orthostatic change and a Valsalva maneuver. The performance of these tests should be standardized, and the influence of confounding variables such as medications, hydration, and antecedent activity should be minimized. Age normative values should be used. The combination of cardiovascular autonomic tests with sudomotor function tests may allow a more accurate diagnosis of DAN (36).

Diabetic patients with features of cardiac autonomic dysfunction such as unexplained tachycardia, orthostatic hypotension, and poor exercise tolerance, or with other symptoms of autonomic dysfunction should be evaluated for the presence of CAN. Screening for CAN should be performed at the diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes, particularly in patients at greater risk of CAN due to a history of poor glycemic control, cardiovascular risk factors, DPN, and macro- and microangiopathic diabetic complications.

Diagnostic criteria and staging of CAN are still being debated. We suggest that the presence of one abnormal cardiovagal test identifies possible or early CAN (29); at least two abnormal HR tests are required for a definite or confirmed diagnosis of CAN (30); and orthostatic hypotension (asymptomatic or symptomatic), in addition to HR test abnormalities, identify a condition of severe or advanced CAN (31). Progressive stages of CAN are associated with an increasingly worse prognosis (34).

可以评估。心血管反射试验的黄金标准临床自主测试。这些试验有良好的敏感性，特异性，和可重复性，是无创性，安全，标准化，并容易进行（35）。然而，Val salva动作不能进行治疗增殖性视网膜病变。最广泛使用的测试评估心脏交感神经功能是基于时域心率（人力资源）反应深呼吸，Val salva动作，和姿势变化。这些测试，人力资源深呼吸有最大的特异性（~ 80%）。心血管交感神经功能是通过测量评估血压体位变化和Val salva动作。执行这些测试应该标准化，

并影响混杂变量，如药物，水化，并先行活动应尽量减少。年龄规范价值应该用。结合心血管自主测试和功能测试可能允许更精确的诊断，但（36）。

糖尿病患者的特点心脏自主神经功能障碍，如原因不明的体位性低血压，心动过速，和运动耐受性差，或与其他植物神经功能紊乱症状应评估是否存在可以。筛选可以执行在诊断2型糖尿病和5年后的诊断1型糖尿病，特别是在病人的风险更大可由于历史的穷人控制血糖，心血管危险因素，糖尿病周围神经病变，以及宏观和微血管并发症的糖尿病。

诊断标准和分期可以还在辩论。我们表明，存在一个异常心跳测试确定了可能或早期可以（29）；至少2异常心率测试，需要一个明确的或可以证实诊断（30）；和体位性低血压（无症状或症状），除了小时试验异常，确定一个条件的严重或先进可以（31）。渐进阶段可以是与日益恶化的预后（34）。

Assessment of potential consequences of CAN.

Attenuation (nondipping) or loss of BP nocturnal fall (reverse dipping) on ambulatory BP monitoring have been associated with CAN and attributed to the disruption of the circadian variation in sympathovagal activity (37). In diabetic patients, nondipping or reverse dipping are independent predictors of cardiovascular events and the progression of diabetic nephropathy. Ambulatory BP monitoring may be useful in patients with CAN to detect nondipping and to address 24-h BP control (Table 1).

评估潜在的后果可以。衰减（非）或损失的血压夜间下降（反向浸渍）动态血压监测已与可以归因于中断的昼夜节律变化的自主神经活动（37）。在糖尿病患者，非或反向浸渍是独立的预测心血管事件和进展糖尿病肾病。动态血压监测可能是有用的患者可以检测非24小时血压控制和地址（表1）。

Table 1

Cardiovascular autonomic tests and suggested indications for their use

表1

心血管自主测试和建议的迹象供他们使用

间期延长是一个独立的预测死亡率在糖尿病患者，是弱相关能（38）（表1）。发病间期延长是多因素和相关包括女性性别，糖尿病，冠心病，控制血糖，收缩压，体重指数，身体活动。

可检测的临床试验研究。时域小时测试和血压反应姿势变化有重复性必要的临床试验。这些试验被用来作为终点在糖尿病控制与并发症试验/流行病学糖尿病干

预和并发症的研究（1 /艾迪克）和其他临床试验。

频域指标得到了运用频谱分析心率变异性的短期（5–7分钟）和长期（24小时）心电图记录提供了一个衡量交感神经和副交感神经调节心率。人力资源的光谱功率在高频区是衡量交感神经调制，而功率谱在低频区域提供了一个衡量交感神经和副交感神经调制。低频血压变异性可能提供了一个衡量交感神经调制。正确评估的意义不同的地区，呼吸应衡量或控制呼吸进行。这些方法，这需要标准化，已被广泛用于研究和作为终点在临床试验。

交感神经流出，在休息和响应各种生理干扰，可以直接测量通过微电极插入分册远端交感神经皮肤或肌肉。该技术是侵入性和耗时的。全身交感神经活性是最准确的评估测量血药浓度的去甲肾上腺素和肾上腺素。

评估心脏迷走神经反射的敏感性（品牌）相结合的信息来源于心率和血压响应药理或血压自然扰动。心脏迷走神经品牌是一个公认的预后指标在一般人群的糖尿病（39）和经常用于研究（表1）。心脏交感神经的品牌可以衡量同时记录肌肉交感神经活动。

核素研究与放射性标记的去甲肾上腺素类似物允许直接定量（[碘- 123 -胍]功能[ ]和单光子发射计算机断层扫描）和定量评估（[ 11 ] -羟基麻黄碱[他]和正电子发

射断层扫描）心脏交感神经的完整性。核素异常相关但也可能存在于患者的正常的心血管自主测试（40）。没有标准化的方法和规范性价值的存在，并提供数

据重复性是有限的。核素研究是适当的探讨影响交感神经功能障碍的心脏代谢和功能是有用的评估心脏交感神经功能的研究。

Issues for future research.

Research issues include: 1) the need for multivariate longitudinal studies to clarify the natural history of CAN in diabetes and pre-diabetes, to evaluate the impact of pharmacologic and lifestyle interventions targeting CAN, and to determine the effect of CAN on clinical outcomes;

2) the refinement and standardization of research measures to permit more widespread use; and 3) the need for studies of combined cardiovascular autonomic and other autonomic measures to improve diagnosis and outcome assessment.

未来研究的问题。研究的问题包括：1）需要多元纵向研究，阐明自然历史可以在糖尿病和

糖尿病前期，评价的影响，药物和生活方式的干预目标，并确定影响可以对临床结果；2）

完善和标准化的研究措施，允许更广泛地使用；3）需要研究合并心血管自主神经和其他自主措施提高诊断及预后评估

GI autonomic neuropathy

GI motor, sensory, and secretory functions are modulated by the interaction of the autonomic (sympathetic and parasympathetic) and enteric nervous systems with underlying rhythmicity generated by the interstitial cells of Cajal located within the smooth muscle. Evaluation of GI autonomic function is difficult in humans, and the diagnosis of GI autonomic neuropathy is often one of exclusion. While irreversible autonomic neuropathy has been regarded as the cause of disordered gut motility in diabetes, recent evidence indicates a heterogeneous picture with a range of fixed pathology and reversible functional abnormalities (41). Acute hyperglycemia slows gastric emptying (GE), while

insulin-induced hypoglycemia accelerates it.

胃肠道自主神经病变

胃肠运动，感觉，和分泌功能调控的互动自主（交感和副交感神经）和肠神经系统的基本节律产生的间质细胞内的平滑肌。评价胃肠道自主神经功能是难以在人类，和诊断胃肠道自主神经病变往往是排斥。而不可逆转的自主神经病变已被视为导致无序的肠道运动的糖尿病，最近的证据表明与异构图片系列固定病理和可逆功能异常（41）。急性高血糖减缓胃排空（通用），而胰岛素诱发低血糖加

速它。

Clinical features.

Disordered GI motility may be associated with GI symptoms, impaired oral drug absorption, poor glycemic control, malnutrition, abnormal postprandial regulation of BP, poor QoL, and a high rate of hospitalization. The relationships with symptoms and CAN are relatively weak (42). Esophageal transit is delayed in ~50% of patients with longstanding diabetes and may be associated with regurgitation, dysphagia, and a propensity for pill-induced esophageal erosions and strictures. Gastroparesis affects ~40% of patients with longstanding diabetes. Symptoms are variable and more common in patients with worse chronic glycemic control and psychological disorders (43).

The rate of GE is a major determinant of postprandial blood glucose changes. In insulin-treated patients, nutrient delivery needs to be matched to the action of the exogenous insulin, and delayed GE is a cause of otherwise unexplained hypoglycemia (44).

Postprandial hypotension occurs frequently in diabetes, and its magnitude is related directly to GE rate. The prevalence of disordered small and large intestinal and anorectal motility is high. Diarrhea may result from rapid or slow transit, which is complicated by bacterial overgrowth and/or disordered secretion. Constipation frequently occurs. Fecal incontinence is not uncommon and is related to reduced and unstable internal anal sphincter tone and impaired rectal compliance and sensation.

临床特点。胃肠动力紊乱可能与胃肠道症状，受损的口服药物的吸收，血糖控制不佳，营养不良，异常调节餐后血压，穷人的生活质量，和较高的住院率。关系的症状和相对薄弱（42）。食管运输延迟~ 50%患者长期糖尿病和可能与返流，吞咽困难，并倾向丸致食管糜烂和狭窄。胃轻瘫影响~ 40%长期的糖尿病患者。症状是可变的，较常见的患者恶化慢性血糖控制和心理障碍（43）。

率的通用电气公司的一个主要决定因素是餐后血糖的变化。在胰岛素治疗的患者，营养交付需要适应行动的外源性胰岛素，和延迟通用电气的一个原因是其他不明原因低血糖（44）。

餐后低血压经常发生在糖尿病，其大小是直接相关的通用电气率。普遍存在的无序小肠、大肠和肛门直肠运动的高。腹泻可能导致快速或缓慢的运输，这是复杂的细菌生长和/或无序的分泌。便秘经常发生。大便失禁是常见的，以减少相关的和不稳定的内部肛门括约肌和肛门直肠和感觉。

Assessment.

Studies of GI autonomic neuropathy, whether performed for clinical, epidemiological, or research purposes, may potentially be focused on GI symptoms, QoL, GI motility/transit, glycemic control, and/or postprandial BP. A number of instruments are available to quantify GI symptoms, including the Diabetes Bowel Symptom Questionnaire. Objective GE measurement is advocated for the diagnosis of gastroparesis. Evaluation of solid emptying is probably more sensitive than that of low-nutrient liquid or semi-solid meals. Medications that may influence GE should ideally be withdrawn, glycemia should ideally be <10 mmol/l throughout the test, and other causes of gastroparesis must be excluded. Failure to demonstrate delayed GE does not necessarily imply that symptoms are not due to “diabetic gastropathy,” but it does help guide drug therapy. Scintigraphy is still regarded as the gold standard technique for GE measurement. Standardization of the meal technique has been improved by the recommendation of a low-fat, egg white meal labeled with technetium-99 (99mTc) sulfur colloid (45). Breath tests using nonradioactive 13 C-acetate or -octanoic acid as a label are appealing options, at least as a screening tool. They are safe, easy to perform, inexpensive, and correlate well with scintigraphy. Ultrasonography (two-dimensional and three-dimensional) is noninvasive and

two-dimensional ultrasound has been validated for measuring emptying of liquids and semi-solids. However, obesity and abdominal gas, together with the necessity for an experienced operator, have limited its widespread use. Surface electrogastrography, used to detect abdominal gastric slow-wave activity, should be regarded as a research tool. A barium meal has no role in quantifying GE.

In the investigation of “diabetic diarrhea” celiac disease, exocrine pancreatic insufficiency and small intestinal bacterial overgrowth must be excluded. Tests of anorectal motor and sensory function are well developed for clinical use.

评估。研究胃肠道自主神经病变，无论是临床，流行病学，或研究的目的，可能会被集中在胃肠道症状，生活质量，胃肠运动/运输，血糖控制，和/或餐后血压。一些文书可量化的胃肠道症状，包括糖尿病，肠道症状问卷。目的是提倡的通用测量诊断胃轻瘫。评价固体排空可能是更敏感比低营养液体或半固体餐。药物会影响葛最好应该撤回，血糖最好应< 10毫摩尔/升整个测试，和其他原因必须被排除的胃轻瘫。未能证明延迟葛并不一定意味着症状不是由于“糖尿病性胃病，但它的确帮助指导药物治疗。显像仍被视为黄金标准的通用电气测量技术。标准化的技术提高了推荐低脂，蛋清粉标记锝- 99（鎝硫胶体（45））。呼吸测试使用非放射性13乙酸盐或辛酸作为一个标签有吸引力的选择，至少作为筛选工具。他们是安全的，易于执行，物美价廉，并与相关显像。超声（二维和三维）是无创性和二维超声已验证测量液体和半固体排空。然而，肥胖和腹部气体，连同必要的有经验的操作者，限制了其广泛使用。表面电，用来检测腹胃慢波活动，应被视为一个研究工具。钡餐没有作用，量化葛。

在调查“糖尿病性腹泻”的腹腔疾病，胰腺外分泌功能不全和小肠细菌过度必须排除。测试的肛门直肠运动和感觉功能以及制定的临床应用。

Erectile dysfunction

The prevalence of erectile dysfunction (ED) among diabetic men varies from 35 to 90%, depending mainly on the various methods applied (46). Neuropathy is one of the leading causes of ED, along with glycation of elastic fibers, peripheral vasculopathy, endothelial dysfunction, psychological factors, drugs, and hormonal changes (47). ED seems to be associated with a higher rate of abnormal sensory and autonomic tests. ED is a predictor of cardiovascular events and is associated with silent myocardial ischemia in type 2 diabetes (48). Alteration of QoL and depressive symptoms seem to precede ED. In clinical trials, ED was more severe and more resistant to treatment in diabetic than in nondiabetic individuals.

Key diagnostic procedures of ED include comprehensive patient history (sexual, medical, drugs, alcohol, tobacco, and psychosocial). The use of validated questionnaires, such as the International Index of Erectile Function and the Sexual Encounter Profile, is the most appropriate method to characterize the frequency and severity of ED symptoms. Other explorations, including evaluation of nocturnal penile tumescence, penile Doppler ultrasound, sacral response, bulbo-cavernosus reflex, dorsal sensory nerve conduction of the penis, amplitude and latency of penile sympathetic skin response, and pudendal nerve

somatosensory-evoked potentials (49), may be useful in patients who do not respond to phosphodiesterase (PDE)-5 inhibitors. Due to the potential risks of adverse or unanticipated drug interactions, cardiac risk factors should be evaluated and managed in all patients with ED and cardiovascular disease. Although ED is a part of autonomic dysfunction, ED prevalence in patients with DAN and the prevalence of DAN among patients with ED have not been analyzed in large epidemiological studies.

勃起功能障碍

勃起功能障碍的患病率（教育）之间的男性糖尿病患者的不同从35到90%，主要取决于各种方法的应用（46）。神经病变是一个重要原因，随着糖基化的弹性纤维，周围血管病变，血管内皮功能障碍，心理因素，药物，和荷尔蒙的变化（47）。教育似乎是与较高的异常感觉和自主测试。教育是预测心血管事件和与无症状性心肌缺血的2型糖尿病（48）。改变生活质量和抑郁症状之前似乎版在临床试验中，埃德更严重和更耐治疗糖尿病比非糖尿病患者。

关键的诊断程序的教育包括全面的病史（性，医疗，药物，酒精，烟草，和心理）。使用验证问卷，如国际勃起功能指数和性接触简介，是最合适的方法来描述的频率和严重程度的症状。其他的探索，包括评价夜间阴茎勃起的阴茎，经颅多普勒超声，骶神经反应，bulbo-cavernosus反射，背感觉神经传导的振幅和潜伏期的阴茎，阴茎皮肤交感反应，和阴部神经体感诱发电位（49），可能是有益的病人谁不应对磷酸二酯酶（磷酸二酯酶）- 5抑制剂。由于潜在的风险，不良或意料之外的药物相互作用，心脏危险因素应当评价和管理所有患者与心血管疾病。虽然是一个部分的自主功能障碍，教育患者患病丹和流行丹患者教育尚未分析在大型的流行病学研究。

Bladder dysfunction

Bladder complications can be due to an alteration of the detrusor smooth muscle, neuronal dysfunction, and urothelial dysfunction. Estimates of the prevalence of bladder dysfunction are 43 to 87% of type 1 diabetic patients and 25% of type 2 diabetic patients. Diabetes duration is

significantly associated with severe incontinence. The correlation between diabetic cystopathy and peripheral neuropathy ranges from 75 to 100%.

Common symptoms include dysuria, frequency, urgency, nocturia, and incomplete bladder emptying. Other symptoms include infrequent voiding, poor stream, hesitancy in initiating micturition, recurrent cystitis, and stress and urgency urinary incontinence. Since urological conditions such as benign prostatic hypertrophy in men or gynecological disorders in women may share the same symptoms, these causes must be excluded by appropriate testing.

Diagnosis should use a validated questionnaire for lower urinary tract symptoms (LUTS). The type of bladder dysfunction is most readily characterized with complete urodynamic testing. Measurement of peak urinary flow rate and postvoid residual volume (PVR) should be considered in diabetic patients with LUTS when diagnosis remains doubtful (50). PVR is ideally measured by portable ultrasound (51). Urodynamic findings include impaired bladder sensation, increased cystometric capacity, decreased (or sometimes unexplained increased) detrusor contractility, and increased PVR (52). Microscopic urinalysis and culture are essential in assessing patients complaining of LUTS. Bladder dysfunction has not been assessed up to now in epidemiological and longitudinal studies or in RCTs.

膀胱功能障碍

膀胱并发症可能是由于改建的逼尿肌平滑肌，神经功能障碍，和尿路功能障碍。估计流行膀胱功能障碍是43至87%的1型糖尿病患者和25%的2型糖尿病患者。糖尿病病程明显与严重的尿失禁。之间的相关性糖尿病和周围神经病变的范围从75到100%。

常见的症状包括排尿困难，频率，紧迫感，夜尿，和不完整的膀胱排空。其他症状包括罕见排尿，贫困流，犹豫不决，开始排尿，复发性膀胱炎，以及压力和紧迫性尿失禁。由于泌尿系统疾病如良性前列腺增生的男性或女性妇科疾病可能有相同的症状，这些原因必须被排除采取适当的测试。

诊断应使用一个经审定的问卷调查的下尿路症状（尿路）。类型的膀胱功能障碍是最容易的特点与完整的尿动力学测试。测量最大尿流率，残余尿量（阻力）应被视为在糖尿病患者的下尿路症状的诊断时仍然怀疑（50）。阻力是理想的测量的便携式超声（51）。尿动力学检查结果包括受损膀胱的感觉，增加膀胱容量，减少（或有时无法解释的增加）逼尿肌收缩，并增加阻力（52）。尿液显微镜和文化是至关重要的评估患者抱怨的下尿路症状。膀胱功能障碍还没有得到评估，至今在流行病学和纵向研究或随机对照试验。

Sudomotor dysfunction

Sweat glands are innervated by the sudomotor, postganglionic, unmyelinated cholinergic sympathetic C-fibers. Sudomotor dysfunction may result in dryness of foot skin and has been associated with foot ulceration (53). Assessment of sudomotor dysfunction contributes to the detection of autonomic dysfunction in DPN.

The quantitative sudomotor axon reflex test (QSART) is capable of detecting distal small fiber polyneuropathy with a sensitivity of >75% (54). QSART may be considered the reference method for the detection of sudomotor dysfunction and is used for clinical and research purposes. Other available techniques for assessment of sudomotor function include the thermoregulatory sweat test, silastic imprint method, the indicator plaster method (55), and the quantitative direct and indirect reflex test (QDIRT) (56). Comparative studies of the sensitivity and specificity of these diagnostic techniques are necessary. Sudomotor function has not yet been assessed in epidemiological and longitudinal studies or in RCTs.

功能障碍

汗腺支配的病人，无髓胆碱能交感神经节后，C -纤维。功能障碍可能导致干燥足部皮肤和已与足溃疡（53）。评估病人的功能有助于检测自主神经功能障碍

的病变。

定量病人的轴突反射试验（qsart）能够检测远端小纤维神经病与敏感性“75%（54）。qsart可能被认为是参考方法检测功能障碍和用于临床和研究目的。其他现有技术的评估功能包括体温调节汗液测试，硅橡胶压印方法，指标石膏法（55），和量化的直接和间接反射试验（qdirt）（56）。比较研究的敏感性和

特异性这些诊断技术是必要的。功能尚未得到评估流行病学和纵向研究或随机对照试验。

EMERGING MARKERS OF DPN: FOCUS ON SMALL FIBERS

It was proposed earlier in this article that if NC is normal, a validated measure (with class 1 evidence) of SFN may be used. We have therefore

assessed the validity of established and emerging measures of SFN and propose a definition.

新兴标记病变：专注于小fibersit是先前提出的在这篇文章中，如果是正常的，一个经审定的措施（1级证据）的单频网可用于。我们已经评估的有效性，建立和新措施的单频网和提出的定义。

Nerve biopsy

Nerve biopsy detects unmyelinated fiber damage while myelinated nerve fiber morphology is still normal in patients with early DPN (57). However, nerve biopsy is an invasive and highly specialized procedure that requires electron-microscopy and cannot be advocated for routine use.

神经活检

神经活检检测无髓纤维损伤而有髓神经纤维形态仍然是正常的患者的早期病变（57）。然而，神经活检是侵入和高度专业化的程序，需要电子显微镜和不能主张日常使用。

Skin biopsy

Skin punch biopsy, a minimally invasive procedure, allows morphometric quantification of intraepidermal nerve fibers (IENF) most commonly expressed as the number of IENF per length of section (IENF/mm). Intra- and inter-observer variability for the assessment of IENF density is good, declines with age, is lower in males than in females, and is not influenced by weight or height (58). The blister technique is a less invasive procedure that assesses innervation of the epidermis alone and shows good agreement with punch biopsy (58).

皮肤活检

皮肤穿活检，微创程序，允许形态量化表皮内神经纤维（ienf）最常用的表示为一些ienf每部分的长度（ienf /毫米）。区域内和跨观察员变异评估ienf密度是好的，随着年龄的下降，是男性比女性低，且不影响体重或身高（58）。泡罩技术是一种微创的程序，评估神经支配的表皮，显示良好的协议，冲床活检（58）。

Diagnostic yield of IENF quantification.