The problem of autonomic neuropathy in diabetic pregnancy

The hazards of pregnancy for both the mother and the fetus in diabetic women with severe retinopathy and nephropathy are well reported. We wish to highlight a poorly recognized problem in the obstetric management of the diabetic mother, that of pregnancy in a patient with autonomic neuropathy. Two such cases are reported where the presence of autonomic neuropathy severely jeopardized the health of the mother, with the loss of the fetus in one, due to occurrence of severe and intractable vomiting. The presence of moderate to severe symptomatic diabetic autonomic neuropathy, particularly with evidence of gastroparesis, may be a relative contraindication to pregnancy.     

A simple diagnostic test for pupillary abnormality in diabetic autonomic neuropathy

A simple portable pupillometer using Polaroid photography has been developed for use in the diagnosis of diabetic autonomic neuropathy. The pupil diameter per cent (PD%), defined as the percentage of iris diameter to which pupil diameter had dilated in darkness, was measured from the instant colour prints. An age-related normal range was constructed from measurements in 163 healthy subjects in whom PD% declined linearly by 3% per decade. The PD% was measured in 15 patients with automatic neuropathy and 12 were identified with abnormally low values indicating a failure of sympathetically mediated dilatation. Results were consistent with the standard television pupillometric technique and had the same high repeatability with a coefficient of variation of 3.2%.     

Vascular calcification, autonomic neuropathy, and peripheral blood flow in patients with diabetic nephropathy

The possibility that digital gangrene in patients with diabetic nephropathy might be due to abnormalities of peripheral blood flow secondary to vascular calcification has been investigated. Twenty patients with renal failure due to diabetic nephropathy were studied. Peripheral blood flow was measured using venous occlusion plethysmography, together with an assessment of medial arterial calcification on plain radiographs of the hands and feet, and transcutaneous oxygen tension (TcPO2). Hallux blood flow was markedly raised (median 22.5, range 11.5-56.5, ml min-1 100-ml-1) compared with non-diabetic control subjects (4.7, 1.1-10.5, ml min-1 100-ml-1; p less than 0.01) and similar to that in diabetic patients with autonomic neuropathy (29.5, 16.7-49.6, ml min-1 100-ml-1). Although vascular calcification was common and extensive in the patients with diabetic nephropathy, TcPO2 measurements in the supine foot were normal and did not indicate tissue ischaemia. We conclude that despite extensive vascular calcification high peripheral blood flow occurs in the feet of these patients at rest together with normal transcutaneous oxygen tension.     

自主神经功能与糖尿病患者左心室功能、心律失常的关系

目的 探讨糖尿病患者自主神经功能与部分心脏合并症之间的关系。方法 采用24小时动态心电图和血压同步监测102例糖尿病患者，左心室功能和结构参数用彩色多普勒超声心动图测定。结果 随SDNN（24小时内全部正常R－R间期的标准差）降低，糖尿病患者的舒张末期二尖瓣口血流频谱A峰与E峰峰值流速的比值（PVA／PVE）、室间隔厚度（IVSTd)、左心室后壁厚度（LVPWTd)、左心室重量指数（LVMI）均增加；二尖瓣前叶活动斜率（MEF）降低，IVSTd/LVPWTd则无变化；严重的心律失常如Lown‘s≥3级的室性心律失常及短阵房速、房颤的发生率也明显增加。上述变化与夜间血压的异常增高相伴随。结论 SDNN低的糖尿病患者心脏受累严重，并可能预示患者日后发生心源性猝死的危险性增加。     

QT prolongation on the electrocardiogram in diabetic autonomic neuropathy

Patients with Type 1 diabetes and autonomic neuropathy have an increased risk of sudden death for which the mechanism remains obscure. Prolongation of the QT interval on the electrocardiogram may occur with sympathetic dysfunction and is also associated with ventricular arrhythmia and sudden death. We have therefore measured the QT interval in patients with Type 1 diabetes with normal, borderline, and definitely abnormal autonomic function tests and in non-diabetic control subjects. The maximum QT interval was measured on 12-lead electrocardiograms recorded at rest and then plotted against the RR interval. The QT interval was above the upper 95% limit for the non-diabetic control subjects in 5 diabetic patients with abnormal autonomic function tests (33%), but in no cases with normal or borderline tests. Multivariate analysis confirmed that autonomic score contributed significantly (p less than 0.025) to the variance in QT interval. The raw Valsalva ratio alone also contributed significantly to the variance in QT interval (p = 0.025). Heart rate variability, heart rate response to standing, age, sex, and the presence of symptoms of autonomic neuropathy did not contribute significantly.     

角膜共聚焦显微镜对糖尿病周围神经病变的诊断价值

目前常用的糖尿病周围神经病变筛查与诊断手段无法做到客观准确以及鉴别高危人群.近年来一种新型检查手段——角膜共聚焦显微镜,可通过无创在体观察和准确定量检测角膜Aδ和C神经纤维的分支密度、长度、迂曲度等,精确诊断糖尿病周围神经病变,且临床研究证明其对糖尿病周围神经病变的早期筛查、预测具有肯定作用,值得在临床推广应用.     

Standing to lying heart rate variation. A new simple test in the diagnosis of diabetic autonomic neuropathy

We have examined the immediate heart-rate response to standing to lying (S-L) in 83 male insulin-dependent diabetic subjects aged 40 +/- 11 years (mean +/-S.D.) who underwent five other cardiovascular autonomic tests. Using a specially devised scoring system, the patients were divided into 3 groups: 54 subjects without autonomic neuropathy; 17 'borderlines'; 12 with autonomic neuropathy. The results were compared with those of 50 sex and age matched controls. We evaluated: S-L1 = ratio between R-R mean before lying and R-R minimum over the first 5 beats after lying; S-L2 = ratio between R-R maximum between the 20th to 25th beat and R-R minimum over the first 5 beats after lying. In controls S-L1 was 1.23 +/- 0.098 (mean +/- S.D.), S-L2 1.56 +/- 0.2. In diabetic subjects without autonomic neuropathy S-L1 was 1.18 +/- 0.096 (p less than 0.01), S-L2 1.50 +/- 0.23. In the autonomic group S-L1 was 1.03 +/- 0.01 (p less than 0.001), S-L2 1.16 +/- 0.086 (p less than 0.001). We propose that the lowest normal and highest abnormal limits of S-L1 are 1.10 and 1.07, respectively, and that normal and highest abnormal limits of S-L2 are 1.23 and 1.41, respectively. We suggest the use of S-L1 as a pure parasympathetic test and S-L2 as a mixed but predominantly sympathetic test in the diagnosis of autonomic neuropathy.     

Cardiac Beat to Beat Variation: Age Related Changes in the Normal Population and Abnormalities in Diabetics*

Abstract: Determination of heart rate variation (RR interval variation) is a non-invasive technique which may be used for assessment of diabetic autonomic dysfunction. Interpretation has been complicated by age changes in the normal population and by uncertainty as to the optimum conditions for the performance of the test. This study was designed to establish a normal age-related range for RR interval variation performed under the simplest conditions (resting, seated) applicable to an outpatient diabetic clinic and to compare these measurements with augmented RR variation due to deep breathing (ARRIV) and with the Valsalva ratio (VR ).
Using an ECG recorder and a computer analysis program, resting RR interval variation (RRIV) was assessed in 100 non-diabetics (N) aged 12–80 years and 60 randomly selected diabetics (D) aged 14–74 years. RRIV, the standard deviation of RR intervals, declined progressively after age 40 in normal subjects. The diabetics had significantly (p < 0.001) reduced RRlV compared with normals; 65% having RRIV values more than 1 SD and 25% more than 2 SD below the age related mean for normals.
RRlV was compared with ARRIV in 54 subjects (N40, 014) and with VR in 84 subjects (N54, D27). There was a significant correlation of RRlV with both indices but RRlV resulted in greater discrimination between N and D than ARRIV or VR. There was no significant correlation between RRlV and duration of diabetes but mean RRlV was significantly reduced in diabetics with peripheral neuropathy compared to those without. In seven diabetics studied both before and after substantial improvement in metabolic control RRlV improved by a mean of 51% (p < 0.005).
Measurement of RRlV is a simple non-invasive technique for assessment of diabetic autonomic dysfunction. Interpretation, however, depends on knowledge of an age-related reference range.     

The Neuropad test: a visual indicator test for human diabetic neuropathy

Aims/hypothesis The commercially available Neuropad test was developed as a simple visual indicator test to evaluate diabetic neuropathy. It uses a colour change to define the integrity of skin sympathetic cholinergic innervation. We compared the results of Neuropad assessment in the foot with established measures of somatic and autonomic neuropathy. Methods Fifty-seven diabetic patients underwent Neuropad assessment, quantitative sensory and autonomic function testing, and evaluation of intra-epidermal nerve fibre density in foot skin biopsies. Results Neuropad responses correlated with the neuropathy disability score (r _s = 0.450, p < 0.001), neuropathic symptom score (r _s = 0.288, p = 0.03), cold detection threshold (r _s = 0.394, p = 0.003), heat-as-pain perception threshold visual analogue score 0.5 (r _s = 0.279, p = 0.043) and deep-breathing heart rate variability (r _s = −0.525, p < 0.001). Intra-epidermal nerve fibre density (fibres/mm) compared with age- and sex-matched control subjects (11.06 ± 0.82) was non-significantly reduced (7.37 ± 0.93) in diabetic patients with a normal Neuropad response and significantly reduced in patients with a patchy (5.01 ± 0.93) or absent (5.02 ± 0.77) response (p = 0.02). The sensitivity of an abnormal Neuropad response in detecting clinical neuropathy (neuropathy disability score ≥5) was 85% (negative predictive value 71%) and the specificity was 45% (positive predictive value 69%). Conclusions/interpretation The Neuropad test may be a simple indicator for screening patients with diabetic neuropathy.     

Diabetic autonomic neuropathy: the prevalence of impaired heart rate variability in a geographically defined population

The prevalence of diabetic autonomic neuropathy and its relationship with other diabetic complications were studied in a geographically defined population. Heart rate variability was measured by a computerized technique at rest and in response to both a single deep breath and a Valsalva manoeuvre. Among 43 Type 1 (insulin-dependent) and 202 Type 2 (non-insulin-dependent) patients results below the 2.5 centile for age-related normal ranges occurred in 9 Type 1 and 32 Type 2 patients (16.7, 95% Cl 12.6 to 21.9, %). Symptomatic autonomic neuropathy was uncommon but was significantly more frequent in Type 1 than Type 2 patients (5 Type 1, 1 Type 2, p less than 0.001 Fisher's exact test). In Type 1 diabetes, cardiovascular autonomic dysfunction was significantly associated with impaired vibration perception and a higher logarithmic urinary albumin concentration and, in Type 2 diabetes, it was associated with a significantly higher body mass index, systolic blood pressure, and logarithm of the urinary albumin and fasting insulin concentrations. The aggregation of these factors with cardiovascular autonomic dysfunction suggests that mortality might be increased in Type 2 patients with asymptomatic autonomic neuropathy.     

Measurement by epigastric impedance of gastric emptying in diabetic autonomic neuropathy

Changes in impedance across the epigastrium form the basis of a new non-invasive method of assessing gastric emptying of liquids. The apparatus is simple to use at the bedside and, in conjunction with conventional investigations, is of value in diagnosing gastroparesis in patients with diabetic autonomic neuropathy and symptoms of recurrent vomiting. We measured gastric emptying of liquids in 22 diabetics aged 33.4 +/- 9 years (mean +/- SD) with severe symptomatic autonomic neuropathy (mean heart rate variability 4.9 +/- 2.2 SD beats/min), and 15 normal controls. Median 'half emptying' time in the diabetics with autonomic neuropathy was prolonged overall but it was not always abnormal (12.25 min, range 6.5-greater than 30 compared to 8.0 min, range 3-17; p less than 0.01). Results in five diabetics with symptoms of recurrent vomiting corresponded with those using conventional radiological methods, confirming gastroparesis in three instances and excluding it in two. The effect of metoclopramide was also studied and was shown to accelerate gastric emptying in some but not all of the patients. Assessment of gastric emptying using the impedance method assists in establishing the diagnosis of gastroparesis and is of value for repeated measurements.     

Cardiac autonomic function in fibrocalculous pancreatic diabetes

Cardiac autonomic function was evaluated in 23 patients with fibrocalculous pancreatic diabetes (FCPD). Though none of the patients had any symptoms referable to autonomic dysfunction, 5 had abnormal heart rate responses. The variability in the heart rate in response to deep breathing was the earliest abnormality found in our patients. Four of the 5 patients had clinical evidence of neuropathy while all 5 had retinopathy and overt nephropathy. We therefore conclude that the autonomic nervous system can be involved in patients with FCDP even as early as 2 years after the onset of the disease, and thus that evaluation of the autonomic nervous system should be part of the routine evaluation of all patients with FCPD.     

Brain oxygenation responses to an autonomic challenge: a quantitative fMRI investigation of the Valsalva manoeuvre

In late age, the autonomic nervous system (ANS) has diminished ability to maintain physiological homeostasis in the brain in response to challenges such as to systemic blood pressure changes caused by standing. We devised an fMRI experiment aiming to map the cerebral effects of an ANS challenge (Valsalva manoeuvre (VM)). We used dual-echo fMRI to measure the effective transverse relaxation rate (R₂*, which is inversely proportional to brain tissue oxygenation levels) in 45 elderly subjects (median age 80 years old, total range 75–89) during performance of the VM. In addition, we collected fluid-attenuated inversion recovery (FLAIR) data from which we quantified white matter hyperintensity (WMH) volumes. We conducted voxelwise analysis of the dynamic changes in R₂* during the VM to determine the distribution of oxygenation changes due to the autonomic stressor. In white matter, we observed significant decreases in oxygenation levels. These effects were predominantly located in posterior white matter and to a lesser degree in the right anterior brain, both concentrated around the border zones (watersheds) between cerebral perfusion territories. These areas are known to be particularly vulnerable to hypoxia and are prone to formation of white matter hyperintensities. Although we observed overlap between localisation of WMH and triggered deoxygenation on the group level, we did not find significant association between these independent variables using subjectwise statistics. This could suggest other than recurrent transient hypoxia mechanisms causing/contributing to the formation of WMH.     

The time course and diurnal variation of postural hypotension in diabetic autonomic neuropathy

Nine diabetic patients (age range 23-67y) with autonomic neuropathy and symptomatic postural hypotension were studied. The time course of the postural drop in blood pressure (BP) was documented firstly at 0900h, prior to breakfast and insulin, and secondly in the afternoon. Seven patients were symptomatic in the morning but only one in the afternoon. The systolic nadir in the morning was lower (p less than 0.02) than in the afternoon. The mean systolic pressure in the first 3 min after standing was no different in the afternoon but it was lower in the 2nd (p less than 0.05), 3rd (p less than 0.02), and 4th (p less than 0.02) 3-min intervals in the afternoon. The time taken to reach the systolic nadir was variable, ranging from 1-12 min. It is concluded that the assessment of the postural fall in BP may be underestimated if measured immediately after standing or if it is measured in the afternoon.     

基于Ewing试验的心率变异性分析对2型糖尿病患者心脏自主神经病变诊断的临床价值研究

目的结合Ewing试验和心率变异性(HRV)分析两种糖尿病心脏自主神经病变(DCAN)诊断方法,探讨基于Ewing试验的HRV分析对DCAN的临床价值。方法选取2012年2月至2013年1月于广东省人民医院内分泌科就诊的T2DM患者47例(T2DM组),及同期体检健康人群19名为正常对照(NC)组。所有受试者在Ewing试验过程中,予心脏搏动法监测HRV。分析静息状态及Ewing试验各项目期间HRV各参数变化,尝试探索基于Ewing试验的HRV诊断模式并评价其临床实用价值。结果以Ewing试验为诊断标准,T2DM组DCAN患病率为55.3%。随机纳入70%T2DM患者(预测组)的HRV指标得到Ewing-HRV诊断组合,包括握力试验时高频功率(HF)、静息状态时低频功率(LF)/HF、Valsalva动作时LF,该模式在其余30%T2DM患者(验证组)中,与Ewing试验诊断方法的符合性:Kappa=0.857,P=0.001,敏感性为100%,特异性为87.5%,阳性预测值为85.7%,阴性预测值为100%。结论基于Ewing的HRV诊断组合(Ewing-HRV法)与经典的Ewing试验的诊断效率高度吻合且该方法无创、受主观因素影响小、简单易行,在进一步探讨和分析的基础上可用于DCAN筛查。     

Median neuropathy at the wrist as an early manifestation of diabetic neuropathy

Aims/Introduction

To elucidate the clinical significance of median neuropathy at the wrist (MN) in patients with diabetes.

Materials and Methods

In total, 340 patients with diabetes who were hospitalized for glycemic control were enrolled in the present study. The diagnoses of MN and diabetic polyneuropathy (DPN) were based on electrophysiological criteria. A total of 187 patients were divided into four subgroups: patients without MN or DPN; patients with MN without DPN; patients with MN and DPN; and patients with DPN without MN. Intergroup comparisons of clinical characteristics and results of nerve conduction studies were carried out.

Results

A total of 71 patients had neither MN nor DPN; 25 had MN, but no DPN; 55 had MN and DPN; and 36 had DPN, but no MN. In comparison with the MN and DPN group, the MN without DPN group included more patients in the early phase of diabetes (diagnosed within the past 5 years) and fewer patients with diabetic microangiopathy. Comparative median nerve conduction studies showed significantly lower motor and sensory nerve conduction velocities, longer F-wave latencies, and smaller sensory nerve action potentials in patients with MN and DPN than in those without DPN.

Conclusions

MN in patients with diabetes could be attributed to an impairment in axonal function at common entrapment sites, and could be used to identify an early manifestation of diabetic neuropathy.     

Morphometry of endoneurial capillaries in diabetic sensory and autonomic neuropathy

Summary Nerve biopsies were obtained from 27 patients with diabetic neuropathy. All had a symmetric distal sensory and autonomic neuropathy or a purely sensory neuropathy. Mean age was 39.8 years (range 23–57 years). Two patients had Type 2 (non-insulin-dependent) diabetes mellitus and the remainder Type 1 (insulin-dependent) diabetes. Morphometric observations on endoneurial capillaries were compared with results from organ donor control cases and from patients with type 1 hereditary motor and sensory neuropathy. The area of the lumen of the capillaries did not differ between the three groups. The area occupied by the capillary endothelial cells in transverse section and the number of endothelial cell nuclei were increased both in the patients with diabetic neuropathy and hereditary motor and sensory neuropathy, as was the thickness of the surrounding basal laminal zone. Closure of endoneurial capillaries in diabetic neuropathy, reported in another study, was not confirmed. Capillary density and nearest-neighbour distances were similar in the diabetic and organ donor control cases. Capillary density was reduced in the patients with hereditary motor and sensory neuropathy, this being related to increased fascicular area consequent upon the presence of hypertrophic changes. The presence of thickening of the pericapillary basal laminal zone and endothelial cell hyperplasia both in diabetic and hereditary motor and sensory neuropathy, the latter being a neuropathy in which a vascular basis can be discounted, makes it difficult to use such changes as an argument favouring a vascular cause for diabetic neuropathy. There were differences in the basal laminal zone between the diabetic and hereditary motor and sensory neuropathy cases suggesting that the reduplicated basal lamina was more persistent in the diabetic patients.     

Mental arithmetic stress as a test for evaluation of diabetic sympathetic autonomic neuropathy

The effects of a 1-min mental arithmetic stress test on heart rate change were studied in 72 Type 1 diabetic patients, 36 without and 36 with diabetic autonomic neuropathy (mean age 33 and 44 yr, respectively), and in 80 matched normal subjects. Variation in hand skin temperature was also recorded in 25 normal subjects and 30 diabetic patients without and 32 with autonomic neuropathy. While mental arithmetic rapidly reduced skin temperature of normal volunteers and of patients without autonomic neuropathy, no effect was found in autonomic neuropath (a drop of 0.63 +/- 0.05 (+/- SE), 0.52 +/- 0.04 and 0.16 +/- 0.02 degrees C (p less than 0.001), respectively). In control subjects and in diabetic patients without and with autonomic neuropathy the heart rate increase was 22.9 +/- 6.8 (+/- SD), 21.4 +/- 8.4 and 7.0 +/- 3.7 beats min-1, respectively (p less than 0.001). The ratio between maximum mental arithmetic-induced heart rate and basal heart rate was 1.29 +/- 0.10, 1.24 +/- 0.10 and 1.07 +/- 0.05 (p less than 0.001) for healthy subjects, non-neuropathic patients, and neuropathic patients. Cut-off values (the low normal limit for these variables) are proposed: skin temperature 0.23 degrees C, heart rate increase 11.6 beats min-1 and heart rate ratio 1.12. Anxiety state, blood glucose concentration (excluding hypoglycaemia), body position, basal heart rate, and age did not interfere with responses to mental arithmetic stress.     

Reproducibility and persistence of neural and adrenal autoantibodies in diabetic autonomic neuropathy

The presence of autoantibodies to autonomic nervous tissue structures is a feature of patients with symptomatic diabetic autonomic neuropathy. It has not been established whether these autoantibodies cause, contribute to or simply reflect nervous tissue damage. Serum samples were tested for the presence of complement-fixing autoantibodies to adrenal medulla, vagus nerve, and sympathetic ganglion cells, to demonstrate: (a) reproducibility of the technique, (b) persistence of the antibodies, and (c) whether or not they occur in patients with non-insulin-dependent (Type 2) diabetes (NIDDM) with neuropathy. Examination of 37 samples, by different observers 2 years apart, revealed a high degree of concordance of both positive and negative results, demonstrating the method of testing to be highly reproducible. Re-testing of 37 patients (by analysing a second blood sample) betwen 0.5 and 2.7 years (mean 1.7 years) after their first test also demonstrated that antibodies, once present, normally persist; and that most patients initially negative remained so. Of 17 neuropathic NIDDM patients, 16 were negative for all three antibodies, indicating their rarity in this group of patients. © 1997 by John Wiley & Sons, Ltd.     

Unawareness of hypoglycaemia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy

Three-hundred and two insulin-treated diabetic patients were questioned about hypoglycaemia using a structured questionnaire interview. Two-hundred and twenty-six patients (75%) had normal symptomatic awareness, 48 (16%) had partial awareness, 21 (7%) had absent awareness of hypoglycaemia, and 7 (2%) denied ever experiencing hypoglycaemia. Patients with complete loss of awareness of hypoglycaemia had diabetes of longer duration; none had a HbA1 concentration within the non-diabetic range. Loss of awareness of hypoglycaemia was associated with an increased incidence of severe hypoglycaemia, 19 (91%) of the patients with absent awareness, and 33 (69%) with partial awareness of hypoglycaemia experiencing severe hypoglycaemia over 1 year compared with only 41 (18%) of patients with normal awareness of hypoglycaemia (p less than 0.001). Cardiovascular autonomic function tests were performed in 226 (75% of the whole group). Of the patients who had diabetes for more than 15 years, 54% (n = 39) with normal awareness of hypoglycaemia, compared with 59% (n = 10) with absent awareness of hypoglycaemia, had evidence of cardiovascular autonomic impairment (NS). Seven (41%) of the 17 patients with absent awareness of hypoglycaemia and diabetes of greater than 15 years duration had no evidence of autonomic dysfunction. Loss of hypoglycaemia awareness is a common problem in patients with insulin-treated diabetes of long duration, is associated with an increased incidence of severe hypoglycaemia, but is not invariably associated with abnormal cardiovascular autonomic function tests.