Subclinical Autonomic Neuropathy Research Articles

A Study on Autonomic Dysfunction in Type 2 Diabetes Mellitus with Peripheral Neuropathy

Abstract Introduction: Subclinical Autonomic Neuropathy is found in association with distal symmetric polyneuropathy in diabetic patients. The Aim of this study was to compare the Cardiac Autonomic Function Test parameters in Type 2 Diabetes Mellitus patients with and without Distal Peripheral Neuropathy. The Primary Objective was to compare the mean of Valsalva ratio in Type 2 Diabetes Mellitus patients with and without Distal Peripheral Neuropathy. The secondary Objective of this study was to find the correlation between Michigan Neuropathic Screening Instrument Score and Autonomic Function test parameters in type 2 Diabetes Mellitus patients. Methods: This was a single centre, cross sectional study conducted from July 2022 to Feb 2023. The study was commenced after obtaining Institute Ethics Committee clearance. Subjects who satisfied the inclusion and exclusion criteria, and gave informed consent for participation in this study were eligible for enrolment. The inclusion Criteria were patients aged between 18 and 65 years with diagnosis of Diabetes mellitus. The number required to study Diabetic patients with peripheral neuropathy was 34 and for Diabetic patients without peripheral neuropathy was 34. Total sample size of 68 patients was taken. Once the patient was enrolled a detailed history, clinical examination, ANS testing and MSNI scoring was done as per attached pre verified proforma duly vetted by institutional scientific committee.Patients were asked to refrain from vigorous exercise for the 24 hours before to the cardiovascular testing as well as from eating, drinking, or smoking for at least 2 hours before the autonomic testing. At the conclusion of the checkup, all antidiabetic and other prescriptions were given. After data collection, test for normality of data was done. Appropriate statistical tests were applied according to data distribution and analysed by using SPSS criteria 2011. Results: A total of 68 patients, 34 with symptoms of Diabetic Peripheral Neuropathy and 34 without Diabetic Peripheral Neuropathy were studied from July 2022 to December 2023. The age, BMI, duration of disease, HbA1c, resting systolic blood pressure and heart rate didn’t show any significant difference between the two groups and thus the groups were comparable. The median (interquartile range) of MNSI score of diabetic patients without neuropathy was 1(1,1) and diabetic patients with neuropathy was 8 (7,9) with p value < 0.005. There was a significant difference in E: I ratio (P<0.0001) between diabetic patients with and without neuropathy. The mean ± SD of Valsalva ratio, in diabetic patients without neuropathy was 1.632 ± 0.115 and with neuropathy was 1.366 ± 0.045. There was a significant difference in Valsalva ratio (P<0.0001). There was a good negative correlation between MNSI score and Valsalva ratio with r= -0.769 and p value < 0.0001 in Type 2 Diabetes mellitus patients. Conclusion: This study found that the Cardiac Autonomic Function Test parameters in Type 2 Diabetes Mellitus patients with and without Distal Peripheral Neuropathy, were significantly deranged in patients with symptomatic DPN. The mean of Valsalva ratio was significantly different in two study groups. The correlation between Michigan Neuropathy Screening Instrument Score and Autonomic Function test parameters in Type 2 Diabetes Mellitus patients showed strong negative correlation. The patients with symptomatic DSN were found to have higher MSNI scores, who in turn were having severe cardiac autonomic dysfunction. Recommendation of Study: Mean Valsalva ratio and MNSI testing are recommended to be used as a screening tool to assess cardiac autonomic functions as a low cost tool in patients of T2DM having symptoms suggestive of DSN.

488-P: Subclinical Autonomic Neuropathy in Uncomplicated Type 2 Diabetes

Cardiac autonomic neuropathy (CAN), a common complication of type 2 diabetes (T2D), is often not detected until late in disease progression. Autonomic nervous system (ANS) dysfunction impairs control of heart rate (HR) and vascular dynamics, manifesting as decreased HR variability (HRV) and impaired blood pressure (BP) regulation. We hypothesized that ANS function is impaired in participants with uncomplicated T2D and correlates with cardiac measures. We measured HRV during cycled breathing and Valsalva and postural HR and BP on overweight physically inactive adults aged 22-70 years with (N=53) and without (N=56) T2D. HRV with cycled breathing and Valsalva was lower in participants with T2D (p=0.007 and 0.005, respectively). HRV with respiration was lower with age >50 years (p=0.0001). HRV with respiration correlated with increased age in T2D but not in overweight control participants. There were no significant changes in postural BP or HR with age >50 years or T2D. Significant correlations between ANS measures and cardiac function were only seen in those with T2D. Valsalva ratio was positively correlated with end-diastolic volume (Pearson’s r 0.58, p=0.02) and stroke volume (Pearson’s r 0.55, p=0.03). HRV with respiration was positively correlated with longitudinal, diastolic peak strain rate (SR) (Pearson’s r 0.68, p=0.007). Postural BP was positively correlated with circumferential and longitudinal, systolic peak SR (Pearson’s r =0.45 and 0.48 and p-value=0.05 and 0.04, respectively) and negatively correlated with radial and circumferential peak strain (Pearson’s r =-0.49 and -0.48 and p-value=0.03 and 0.03, respectively). These data suggest subclinical CAN associated with cardiac dysfunction is present in people with otherwise uncomplicated T2D and is exacerbated with age. Detecting CAN changes early may identify people at risk for cardiac disease and inform targeted intervention to restore cardiometabolic health in people with T2D. Disclosure A.Johnston: None. L.A.Abushamat: None. D.Enge: None. A.J.Barker: None. E.W.Clark: None. D.Rafferty: None. J.G.Regensteiner: None. J.E.B.Reusch: Advisory Panel; Medtronic. Funding American Diabetes Association (1-21-CMF-003 to L.A.A.); National Institutes of Health (T32DK120520-01A1); U.S. Department of Veterans Affairs (CX001532)

Interpreting resting heart rate variability in complex populations: the role of autonomic reflexes and comorbidities.

Resting heart rate variability (HRV) is an important biomarker linking mental health to cardiovascular outcomes. However, resting HRV is also impaired in autonomic neuropathy, a common and underdiagnosed complication of common medical conditions which is detected by testing autonomic reflexes. We sought to describe the relationship between autonomic reflex abnormalities and resting HRV, taking into consideration medical comorbidities and demographic variables. Participants (n=209) underwent a standardized autonomic reflex screen which was summarized as the Composite Autonomic Severity Score (CASS) and included measures of reflexive HRV, e.g., heart rate with deep breathing (HRDB). Resting HRV measures were: pNN50 (percentage of NN intervals that differ by>50ms) and cvRMSSD (adjusted root mean square of successive differences). In univariate analyses, lower resting HRV was associated with: older age, higher CASS, neuropathy on examination, hypertension, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, and psychiatric disease. Adaptive regression spline analysis revealed that HRDB explained 27% of the variability in resting HRV for participants with values of HRDB in the normal range. Outside this range, there was no linear relationship because: (1) when HRDB was low (indicating autonomic neuropathy), resting HRV was also low with low variance; and (2) when HRDB was high, the variance in resting HRV was high. In multivariate models, only HRDB was significantly independently associated with cvRMSSD and pNN50. Subclinical autonomic neuropathy, as evidenced by low HRDB and other autonomic reflexes, should be considered as a potential confounder of resting HRV in research involving medically and demographically diverse populations.

O-AD005. Diabetic cardiovascular autonomic neuropathy

Introduction . Diabetic neuropathies are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves. Cardiac autonomic neuropathy (CAN) represents a serious complication associated with diabetic neuropathies. Methods . This is a descriptive prospective cross-sectional hospital-based study. The study population included type 1 and type 2 diabetic patients admitted to the cardiac care unit in ELshaab Teaching Hospital with acute coronary syndrome over a period of two years, from April 2017 to April 2019. Results . A total of 49 males (65.33%) and 26 females (34.67%) were included in the study. CAN was detected in 94.67% of the studied group. Conclusion . An incidence of 94.67% cardiovascular autonomic neuropathy in our sample indicates a high occurrence of this syndrome among our diabetic patients. Poor glycemic control is a common feature among our studied group. Sub-clinical autonomic neuropathy can be detected early using autonomic function tests.

Correlation of body fat percentage with the occurrence of subclinical cardiac autonomic neuropathy in hypothyroidism

Background: The incidence of cardiac-related mortality is increasing in hypothyroid. Aims and Objective: The objectives of the study were to assess the incidence of cardiac autonomic neuropathy (CAN) in hypothyroid and its correlation with body fat levels. Materials and Methods: Thirty diagnosed hypothyroid in the age group of 25–50 of both genders were involved (n = 30). Age- and sex-matched euthyroid were controls (n = 30). CAN was evaluated in terms of the presence of resting tachycardia, loss of sinus arrhythmia by calculating deep breath difference, and heart rate response to Valsalva maneuver by calculating Valsalva ratio recorded by electrocardiogram in the lead II. Body fat was measured using skin calipers at four sites using Durnin and Womersley equation. The correlation was assessed using Pearson’s matrix. Results: The study shows in hypothyroid among 30 (n = 30), 27% (n = 8) were having borderline CAN. Among euthyroid 13% (n = 4) and 10% (n = 3) were having borderline and definitive CAN. The study shows a negative correlation exists between body fat percentage and deep breathing difference and Valsalva ratio. (r = ‒0.20 P = 0.289, r = ‒0.19 P = 0.30). Conclusion: The incidence of subclinical CAN is more in hypothyroid than euthyroid which shows a negative correlation with body fat level.

Infectious diseases causing autonomic dysfunction.

To review infectious diseases that may cause autonomic dysfunction. Review of published papers indexed in medline/embase. Autonomic dysfunction has been reported in retrovirus (human immunodeficiency virus (HIV), human T-lymphotropic virus), herpes viruses, flavivirus, enterovirus 71 and lyssavirus infections. Autonomic dysfunction is relatively common in HIV-infected patients and heart rate variability is reduced even in early stages of infection. Orthostatic hypotension, urinary dysfunction and hypohidrosis have been described in tropical spastic paraparesis patients. Varicella zoster reactivation from autonomic ganglia may be involved in visceral disease and chronic intestinal pseudo-obstruction. Autonomic and peripheral nervous system dysfunction may happen in acute tick-borne encephalitis virus infections. Hydrophobia, hypersalivation, dyspnea, photophobia, and piloerection are frequently observed in human rabies. Autonomic dysfunction and vagal denervation is common in Chagas disease. Neuronal depopulation occurs mainly in chagasic heart disease and myenteric plexus, and megacolon, megaesophagus and cardiomyopathy are common complications in the chronic stage of Chagas disease. Parasympathetic autonomic dysfunction precedes left ventricle systolic dysfunction in Chagas disease. A high prevalence of subclinical autonomic neuropathy in leprosy patients has been reported, and autonomic nerve dysfunction may be an early manifestation of the disease. Autonomic dysfunction features in leprosy include anhidrosis, impaired sweating function, localised alopecia ,and reduced heart rate variability. Urinary retention and intestinal pseudo-obstruction have been described in Lyme disease. Diphtheritic polyneuropathy, tetanus and botulism are examples of bacterial infections releasing toxins that affect the autonomic nervous system. Autonomic dysfunction may be responsible for additional morbidity in some infectious diseases.

Upper extremity subclinical autonomic and peripheral neuropathy in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune, multiorgan disease that affects connective tissues of many organs or systems, including the nervous system, where it affects the autonomic, the peripheral, and the central nervous system. The aim of this study was to investigate the association of subclinical autonomic and peripheral neuropathy with SLE and to correlate neurophysiological parameters with clinical and laboratory data. Fifty-six SLE patients were included in this study. In addition, thirty age-matched and sex-matched healthy participants served as a control group. Exclusion criteria included patients having symptoms or signs indicating autonomic dysfunction or peripheral neuropathy. Also, endocrinal, toxic, compression, and traumatic neuropathies were excluded. Patients were assessed clinically and by laboratory investigations. Neurophysiological assessment included sympathetic skin response of the median nerve including latency and amplitude. In addition, nerve conduction study of both median and ulnar nerves was performed including motor distal latency, amplitude, nerve conduction velocity, and distal sensory latency. Pure sensory abnormality was detected in one patient, whereas pure motor neuropathy was found in 19 patients. Mixed sensory–motor abnormalities were detected in two patients. Sympathetic skin response was not elicited in 13 patients, whereas latency and amplitude abnormalities were detected in 11/43 and 9/43 patients, respectively. Sympathetic and axonal neuropathy was not correlated with the disease duration or the disease activity. The pattern of neuropathy in SLE is mainly axonal. Also, the sympathetic nervous system is affected in lupus patients with a rate of up to 40% of the cases.

P15.3 Subclinical autonomic neuropathy in infant-juvenile diabetes. A community-based study

P15.3 Subclinical autonomic neuropathy in infant-juvenile diabetes. A community-based study

P35.13 Subclinical cardiovascular autonomic neuropathy in patients with diabetic somatic neuropathy

P35.13 Subclinical cardiovascular autonomic neuropathy in patients with diabetic somatic neuropathy

Time-Domain Analysis of Heart Rate Variability in Diabetic Patients with and without Autonomic Neuropathy

The normal heart rate is determined by dynamic interaction between the spontaneous cardiac impulse generated by the sinoatrial (SA) node and conflicting influences of the sympathetic and parasympathetic nervous systems on the conducting tissue of the heart. The rate of spontaneous depolarization of the SA node is itself affected by its metabolic milieu and in the longer term, by hormonal influences. Normal resting heart rate is maintained by the tonic influence of the parasympathetic vagus nerve, and acceleration of the heart rate is affected both by the inhibition of vagal influence and the stimulation of the sympathetic nervous system. The activity of the autonomic is also governed by moment-to-moment changes in blood pressure and respiration, which alter heart rate continuously. The resultant heart rate is the summation of all these influences and thus inherently unpredictable on a beat-to-beat basis. Recent advances in technology have enabled accurate recordings and the automated analysis of 24-hour ECG to detect beat-to-beat variability, providing not only more detailed, but much more accurate and precise information than the earlier tests. Heart rate variability (HRV) decreases with age, and shows a circadian variation, being maximum during sleep. It is also rate dependant, the heart rate showing more variability at lower heart rates. The loss of this beat-to-beat variability is a sign of disease. It has long been known that cardiovascular autonomic diabetic neuropathy (CADN) is associated with a loss of heart rate variability. These patients have a poor cardiovascular prognosis, with a 5-year mortality greater than 50%. Some of this may be attributed to micro- or macrovascular disease, however, a recent study has shown the relatively poor prognosis of patients with CADN in the absence of clinically detectable micro- or macrovascular conditions. Clinically detectable autonomic failure is usually evident many years or decades after the onset of diabetes. It is likely that these patients develop subtle deficits in HRV much earlier, and these may include diminution in time-domain analysis. Detection of such changes may be used as markers of pathology, particularly to study the benefits of therapeutic interventions. Thus, the aim of this work was to study HRV in diabetic patients with clinical and sub-clinical autonomic neuropathy (AN), and to determine whether HRV in patients with sub-clinical AN is abnormal in comparison to normal controls.

Decreased prorenin processing develops before autonomic dysfunction in type 1 diabetes.

It is well documented that diabetic patients with chronic complications have decreased renin secretion and elevations in the renin precursor prorenin. It is uncertain, however, whether the abnormal processing of prorenin is reflective of microvascular disease, hypertension, or autonomic neuropathy. Dechaux et al. (Transplant Proc. 18:1598-1599, 1986) observed abnormalities in prorenin processing in uncomplicated diabetes and suggested that it was the result of subclinical autonomic neuropathy. To test this hypothesis, we measured renin, prorenin, and autonomic function in early type 1 diabetes at a time when there is little or no microvascular disease or hypervolemia. Thirty-seven patients (10 males, 27 females) enrolled 2-22 months after diagnosis in a longitudinal study in which renin, prorenin, and autonomic function were measured annually for 3 years. Forty-one age-matched control subjects were also studied. PRA in the diabetic patients at the time of the second and third evaluations was 1.71 +/- 0.24 ng angiotensin I/mL x h and 1.67 +/- 0.24 ng angiotensin I/mL x h, respectively, significantly lower (P < 0.05) than that of the control subjects in whom PRA was 2.96 +/- 0.38 ng angiotensin I/mL x h. Prorenin was not different in the diabetic patients in comparison with controls. The renin to prorenin ratio in the diabetic patients at the time of the first, second, and third evaluations was 0.260 +/- 0.03, 0.235 +/- 0.05, and 0.227 0.05, respectively, significantly lower (P < 0.01) than in control subjects in whom the renin to prorenin ratio was 0.475 +/- 0.08. Despite this, at the time of the first and second evaluations, there was no evidence of autonomic dysfunction and no correlation between any test of autonomic function and the renin to prorenin ratio. At the time of the third evaluation, however, the intermediate frequency (0.04-0.15 Hz) power spectra while patients were supine (an index of sympathetic modulation of heart rate variability) showed a highly significant (P < .001) correlation with the renin to prorenin ratio. High frequency (0.15-0.40 Hz) spectra from supine patients at the third evaluation also correlated with the renin to prorenin ratio (P < 0.01). We conclude abnormal processing of prorenin develops in diabetic patients prior to microvascular disease, even before the first evidence of autonomic dysfunction. Although the latter may play a contributory role, additional as yet unidentified mechanisms seem to interrupt the processing of prorenin in early diabetes.

Urinary albumin excretion rate is independently related to autonomic neuropathy in type 2 diabetes mellitus.

To evaluate if urinary albumin excretion rate (UAER) is independently related to subclinical autonomic neuropathy in type 2 diabetes. A controlled cross-sectional study. Primary health care centre. Consecutive recently diagnosed (< 1 year) type 2 diabetic patients (group A, n = 150) and patients with long-standing (median 11 years) type 2 diabetes (group B, n = 146) chosen at random. A nondiabetic control group (group C, n = 150) matched for age and gender to group A. Neuropathy by cardiovascular reflex tests and UAER by nephelometry. Univariate statistics in group A + B (t-test chi 2- or McNemars test) with Valsalva and breathing ratios as categorical grouping variables and the independent variables gender, smoking, systolic and diastolic blood pressure, fasting serum cholesterol, HDL cholesterol, triglycerides, haemoglobin A1c, glucagon stimulated C-peptide, fasting and postload 1 and 2 h blood glucose and serum insulin, UAER, coronary heart disease and congestive heart failure. Logistic regression analyses in group A + B with Valsalva and breathing ratios as dependent categorical variables and age, systolic blood pressure, congestive heart failure, coronary heart disease, fasting blood glucose, serum triglycerides and UAER as independent variables. Compared to nondiabetic subjects the diabetic patients of both groups were at increased risk of neuropathy as judged by the Valsalva ratio (P < 0.01). In known diabetic patients with a UAER > or = 30 mg 24-1 h neuropathy was more common than amongst their normoalbuminuric counterparts (Valsalva test P = 0.007, breathing test P = 0.02). In logistic regression analysis UAER independently explained abnormal Valsalva (P = 0.015) and breathing tests (P = 0.04) in the group A + B. UAER is independently related to subclinical autonomic neuropathy in type 2 diabetes.

Renal and cardiovascular predictors of 9-year total and sudden cardiac mortality in non-insulin-dependent diabetic subjects.

The objective was to evaluate the impact of urinary albumin excretion rate (UAER), glomerular filtration rate (GFR) and subclinical autonomic neuropathy (SANP) on 9-year total (TM) and sudden cardiac mortality (SCM) in recently diagnosed (< 1 year; RD; n = 150) and known (mean duration 11 years; KD; n = 146) NIDDM subjects. The study was prospective and controlled (n = 150). Mortality predictors were analysed by logistic regression analysis. The dependent variables were TM and SCM, the predictors were UAER, GFR, SANP, age, gender, BMI, mean arterial pressure (MAP), fasting serum cholesterol, HDL-cholesterol, triglycerides, insulin, haemoglobin A1c, diabetes duration, QTc-interval (ECG), coronary heart disease (CHD), peripheral vascular disease (PVD), cerebrovascular disease (CVD), congestive heart failure (CHF), antihypertensive therapy, and smoking habits. CHD predicted TM and SCM in both RD (P = 0.041 and 0.029) and KD (P = 0.034 and 0.006). PVD predicted TM and SCM in KD only (P = 0.001 and 0.003). CVD predicted TM and SCM in RD only (P = 0.001 and 0.017). In RD male gender (P = 0.049), fasting serum cholesterol (P = 0.007) and CHF (P = 0.001) predicted TM and in kDa haemoglobin A1c (P = 0.004), age (P = 0.001) and MAP (P = 0.014) predicted TM. Serum triglycerides predicted SCM in both RD and kDa (P = 0.001 and 0.003). SANP predicted TM (P = 0.009) and SCM (P = 0.044) in KD only. GFR (inverse value) predicted TM and SCM (P = 0.04 and 0.027) in kDa only. The UAER did not predict mortality in the diabetic subjects. SANP and a slightly reduced GFR still in the normal range predicted mortality in KD. Microalbuminuria (30 < UAER < 300 mg/24 h) did not independently predict 9-year mortality in the NIDDM subjects studied.

Peripheral autonomic nerve dysfunction in asymptomatic leprosy contacts

In endemic areas, subclinical autonomic nerve dysfunction may be a manifestation of infection with M. leprae and possibly allow detection before progression to clinical disease. Vasomotor reflex (VMR) testing was performed in 36 asymptomatic leprosy contacts (24 household contacts, 12 hospital contacts) and 47 age- and sex-matched controls in Pokhara, Nepal. Mean age was 30 years, two thirds were male. A Moor instruments DRT4 laser doppler monitor was used for velocimetry of microvascular blood flow. The flow reduction following an inspiratory gasp was recorded from finger and toe tips. Mean percent reduction was 57.8 (standard deviation 14.6) among household contacts, 61.9 (17.5) among hospital contacts and 66.8 (7.8) among controls ( p=0.001 by analysis of variance). The prevalence of abnormal test results was 54% among household contacts, 42% among hospital contacts and 15% among controls ( p=0.0005 by chi-square test for trend). Subclinical autonomic neuropathy is common among healthy contacts of leprosy patients. Prospective studies are now needed to clarify to what extent abnormal VMR tests predict the risk of progression to clinical disease.

Hormonal, renal, and autonomic nerve factors involved in the excretion of sodium and water during dynamic salt and water loading in hypoxaemic chronic obstructive pulmonary disease.

Some patients with hypoxaemic chronic obstructive pulmonary disease (COPD) develop sodium and water retention and a subclinical autonomic neuropathy. The possibility that these might be associated has been investigated. The ability of 24 patients with COPD to excrete a 6 ml/kg 2.7% intravenous saline or 15 ml/kg oral water load was studied and changes in plasma electrolyte levels, osmolality, plasma aldosterone and vasopressin levels, urinary volume and sodium content, glomerular filtration rate, renal blood flow, and cardiovascular autonomic nerve function were measured. Patients were divided into groups of eight: those in group A (controls) had mild COPD with a Pa02 of > 9 kPa and no oedema, patients in group B were more hypoxaemic but had never been oedematous, whilst those in group C were hypoxaemic and mildly oedematous at the time of the study. Patients in groups B and C excreted less sodium and water during saline loading and a lesser proportion of the water load. Patients in group C had a reduction in renal blood flow and glomerular filtration rate and all had a subclinical autonomic neuropathy, which was also found in three patients in group B. Their plasma aldosterone level was raised but did suppress appropriately on saline loading. Vasopressin levels were abnormally raised for the osmolality in patients in group C and in those with autonomic dysfunction throughout the water load and at 240 minutes after the salt load. Sodium and urine excretion was highly correlated with autonomic dysfunction, aldosterone levels at time zero, and renal blood flow. The 11 patients with autonomic dysfunction were more likely to be oedematous, more hypoxaemic, excreted much less urine and sodium, had lower glomerular filtration rate and renal blood flow, and higher aldosterone and vasopressin levels than the remaining patients. In patients with COPD the inability to excrete sodium and water is multifactorial. This is the first study to show that autonomic dysfunction is at least associated and might play an important part in the impaired sodium and water homeostasis seen in patients with severe COPD.

The QTc interval, autonomic neuropathy and mortality in hypoxaemic COPD

Patients with hypoxaemic chronic obstructive pulmonary disease (COPD) have a subclinical autonomic neuropathy. Autonomic neuropathy has been associated with a prolonged electrocardiograph QTc interval and risk of ventricular arrhythmias and death. We studied cardiovascular autonomic nerve function and QTc interval at rest and during stress (a valsalva manoeuvre) in 34 patients with hypoxaemic COPD who were followed up after 2 yr. Seventeen patients had a subclinical autonomic neuropathy (group AN) and the remaining 17 were normal (group C). Group AN were significantly more hypoxaemic ( PaO 2 7·3 ± 0·3 compared to 9·2 ± 1·8, P<0·05), had a lower FEV 1 and had a longer QTc at rest (0·43 ± 0·01 compared to 0·40 ± 0·01, P<0·01) and at peak valsalva (0·44 ± 0·01 compared to 0·41 ± 0·01, P<0·05). When analysed after 2 yr, there were two deaths in group C and seven deaths in group AN. The QTc was abnormal >0·44 s at rest and at peak valsalva stress in five of group AN, three of these five patients died. QTc was normal at rest but abnormal at peak valsalva stress in eight further patients. This included three further patients from group AN of whom two had died and five group C patients which included both the group C deaths. The presence of autonomic neuropathy and QTc prolongation (>0·44 s) at rest was significantly associated ( P<0·05). Likewise QTc prolongation at the peak of a valsalva stress was significantly associated with death at 2 yr follow-up ( P<0·01) with an odds ratio of 11·1. Patients with hypoxaemic COPD, particularly those with a parasympathetic autonomic neuropathy have evidence for a prolongation of the QTc interval which is associated with an increased mortality risk.

Pupil size in diabetes.

Sympathetic function was studied in 101 diabetic children and 102 age and sex matched control children, as part of a longitudinal study of the evolution of microvascular disease in the population of diabetic children and adolescents in Avon County. The median (range) age of the diabetic population was 13.5 (6.0-17.2) years, the duration of diabetes was 4.0 (0.4-13.9) years, and glycated haemoglobin (HbA1) was 10.9 (7.0-18.1)%. Pupillary adaptation in darkness, as an index of sympathetic neuropathy, was measured using a Polaroid portable pupillometer. Diabetic children had a significantly smaller median pupillary diameter, measured as the pupil/iris ratio and expressed as a percentage, than control children (median (range) 62.9 (50.3-72.1) v 65.9 (52.2-73.8)). Pupillary diameter was significantly related to diabetes duration (r = -0.22), HbA1 (r = -0.34), systolic blood pressure (r = -0.25), diastolic blood pressure (r = -0.49), and mean albumin/creatinine ratio on random urine samples (r = -0.26). Pupillary diameter was not related to age (r = -0.1). Eight (7.9%) diabetic and four (3.9%) control children were identified as having abnormal pupillary dilation in darkness. In comparison with the rest of the diabetic population, these diabetic children had longer diabetes duration and poorer glycaemic control. Polaroid pupillometry has demonstrated subclinical autonomic neuropathy in a population of diabetic children and adolescents. These abnormalities were related to poor metabolic control, long diabetes duration, and also to other indices of microvascular disease.

Detection of subclinical autonomic neuropathy in constipated patients using a sweat test.

Chronic idiopathic constipation may be the result of an autonomic neuropathy. This hypothesis was tested in 23 constipated patients and 17 age matched controls, using the acetylcholine sweat spot test devised to test autonomic integrity in diabetes. Acetylcholine (0.01%) was injected in the dorsum of the foot painted with a mixture of starch and iodine. Active sweat glands appeared on the surface of the skin as small black dots which were photographed and counted, using a grid with 60 subareas. Two measurements were made: the number of dots per unit subarea (sweat spot test score) and the % number of abnormal subareas (with less than six spots). These two parameters were correlated. The median sweat spot test score was 9.53 in patients and 13.92 in controls (p = 0.0001), the receiver operating characteristic curve showing that a score of 12 delimited normal and abnormal subjects. Increasing age was correlated with a low score in patients, probably because of prolonged symptoms. Seventy per cent of patients and one control had a borderline or abnormal number of subareas. These results suggest that idiopathic constipation is associated with a degree of autonomic denervation. The sweat spot test is an easy, inexpensive method to test this hypothesis and deserves a place in the clinical assessment of slow transit constipated patients.

Cardiovascular autonomic nerve function in patients with hypoxaemic chronic obstructive pulmonary disease

Intraneural hypoxaemia is recognized as a pathogenic mechanism in diabetic neuropathy. A similar pathophysiological process may occur in chronic obstructive pulmonary disease (COPD). Autonomic neuropathy is not recognized in COPD. We compared 96 patients with hypoxaemic COPD to 22 age-matched control subjects to see whether autonomic dysfunction occurs in COPD and whether there was any correlation with the severity of hypoxaemia. The cardiovascular autonomic tests consisted of heart rate responses (mainly parasympathetic function) to a Valsalva manoeuvre, deep breathing and postural change and blood pressure responses (mainly of sympathetic origin) to postural change and sustained handgrip. Early autonomic neuropathy is defined as one abnormal test and definite autonomic neuropathy as two abnormal tests according to the normal range. These autonomic tests were reproducible in our study population. Although the symptoms and signs of autonomic neuropathy were rare, definite autonomic dysfunction was found in 35%, and early autonomic neuropathy in a further 47%, of patients whose arterial oxygen tension (PaO2) was less than 8 kPa (60 mmHg). Only 18% of the control group had evidence of an age-related early autonomic dysfunction. Parasympathetic autonomic dysfunction was significantly correlated with PaO2 whilst the sympathetic tests were relatively normal. Correction of hypoxaemia for one hour or administration of ipratropium bromide or terbutaline had no effect on autonomic function. Subclinical autonomic neuropathy is a feature of hypoxaemic COPD. Its importance in the disease process and its role in prognosis needs evaluation.

The perception of angina in diabetes: Relation to somatic pain threshold and autonomic function

Silent ischemia is common in diabetic patients with coronary heart disease. These patients may also have more subtle alteration in the perception of angina as reflected by prolongation of anginal perceptual threshold—the time from onset of 0.1 mV ST segment depression to the onset of chest pain during treadmill exercise. Silent ischemia may be associated with a generalized hyposensitivity to pain, although the pathophysiologic mechanism is obscure. The purpose of the present study was to determine whether diabetic patients with prolonged anginal perceptual thresholds are also hyposensitive to painful stimuli and to investigate whether this is associated with autonomic neuropathy. Nineteen diabetic and 25 nondiabetic patients with exertional angina were exercised on a treadmill to measure anginal perceptual threshold. Somatic pain threshold was measured by calf sphygmomanometry. The cuff was inflated rapidly until pain occurred, and six repeat inflations were done to test reproducibility. Because there was no significant difference between measurements (coefficient of variation =0.156) the mean value for each patient provided a measure of somatic pain threshold. The diabetic group had a longer anginal perceptual threshold (138 ± 64 seconds vs 34 ± 51 seconds, p < 0.001), which correlated positively with the somatic pain threshold ( r = 0.5, p = 0.03); patients with more prolonged anginal perceptual thresholds tended to have higher somatic pain thresholds. In the diabetic group anginal perceptual ( r = −0.3, p = NS) and somatic pain ( r = −0.4, p = 0.05) thresholds tended to increase as the ratio of peak to minimal heart rate during the Valsalva maneuver fell below 1.21, but these variables were unrelated in the nondiabetic group. Thus like patients with silent ischemia, diabetic patients in whom the perception of angina is impaired tend to have heightened somatic pain thresholds. This is associated with subclinical autonomic neuropathy, although whether neuropathic mechanisms account for the perceptual dysfunction in silent ischemia remains to be determined.