Frits W. Bertelsmann

Glucose tolerance and other determinants of cardiovascular autonomic function: the Hoorn Study

Aims/hypothesis. Currently, three categories of measures are used to assess cardiovascular autonomic dysfunction: measures of the Ewing-test, measures of heart-rate variability, and measures of baroreflex sensitivity. We studied the determinants of these measures obtained from cardiovascular autonomic function tests in the Hoorn Study. Methods. The study group (n = 631) consisted of a glucose-tolerance-stratified sample from a 50- to 75-year-old group of people. Cardiac cycle duration (RR interval) and continuous finger arterial pressure were measured under three conditions: during (a) spontaneous breathing, (b) six deep breaths over one minute, and (c) an active change in position from lying to standing. From these readings, ten measures of autonomic function were assessed (three Ewing, six heart-rate variability and one baroreflex sensitivity). As possible determinants we considered age, sex, glucose tolerance, cardiovascular disease, use of anti-hypertensive drugs, anthropometric factors, metabolic factors and lifestyle factors. Results. Multivariate analysis showed that eight of ten cardiovascular autonomic function measures were most strongly associated with glucose tolerance. Furthermore, measures were moderately associated with age, sex, waist-to-hip ratio, use of anti-hypertensive drugs, and insulin. The measures were weakly associated with coronary artery disease but not with lipids. The strongest determinants seemed to differ between subjects with and without diabetes: in the non-diabetic subjects the most strongly associated were age and use of anti-hypertensive drugs and in subjects with diabetes, insulin. No consistent differences in association between the three categories of measures were observed. Conclusion/interpretation. The strongest determinants of autonomic function were age, presence of diabetes and use of anti-hypertensive drugs. [Diabetologia (2000) 43: 561–570]

Clinical examination versus neurophysiological examination in the diagnosis of diabetic polyneuropathy.

Several methods have been used to diagnose diabetic polyneuropathy and to quantitate the degree of affection of peripheral nerves. Using a newly developed scoring system we compared bedside clinical examination with neurophysiological examination in a group of 78 diabetic patients. Individual scores for clinical examination were significantly correlated with scores for neurophysiological examination (r = 0.7, p < 0.0005). All 78 patients had at least one clinical symptom or sign of polyneuropathy. Clinical examination indicated polyneuropathy in three patients with neuropathic complaints, while neurophysiological examination in these patients showed no abnormalities. In 12 out of 14 patients with normal neurophysiological sensory nerve function, clinical examination showed at least one abnormal sensory modality. Comparing the four different sensory modalities, light touch sense and pinprick sense indicated polyneuropathy better than vibration or position senses. An abnormal Hoffmann reflex of the soleus muscle was always associated with a decreased or absent ankle jerk. The scoring system for the clinical examination proved useful for diagnosing and quantitating the severity of diabetic polyneuropathy. Clinical sensory deficits could not be inferred from the results of neurophysiological testing of sensory nerve function. Pinprick sense, light touch sense, and ankle jerks were the most important parameters in the clinical diagnosis of diabetic polyneuropathy.

Methods for assessing diabetic polyneuropathy: validity and reproducibility of the measurement of sensory symptom severity and nerve function tests.

The usefulness of sensory symptoms in the assessment of diabetic polyneuropathy is unclear. In the present study, we studied the hypothesis that pain is associated with small nerve fibre function, and that sensory alteration is associated with large nerve fibre function. In addition, we assessed the reproducibility and the ability to detect changes in clinical status over time of the nerve function tests currently used in clinical trials. Patients (78) with stable diabetic polyneuropathy were examined on three separate occasions with a test-retest interval of 17 and 52 weeks. Small nerve fibre function was measured using temperature discrimination thresholds for warmth (TDTwarmth) and cold (TDTcold). Large nerve fibre function was measured by testing sensory and motor nerve conduction velocities (SNCV and MNCV) and vibration perception thresholds (VPT). Neuropathic pain was only significantly associated with TDTcold, and with the MNCV of the tibial nerve. Sensory alteration was associated with almost all nerve function tests except the SNCV and MNCV of the ulnar nerve. The measurements of symptom severity and the nerve function tests all proved to be sufficiently reproducible. The standardized smallest detectable difference on group level (SDD) of the measurement of sensory alteration and neuropathic pain were almost the same (9% and 12%, respectively). Among the nerve function tests, the SNCV and MNCV had the smallest SDD (3-4%), and were, therefore, potentially the most responsive instruments. The SDD of the TDT was greater than the VPT (9-14% vs 21-28%, respectively). In conclusion, neuropathic pain was not associated with small nerve fibre function, and sensory alteration was associated with both large and small fibre function. In addition, the standardized measurement of symptom severity, the SNCV and MNCV tests, and the VPT test appear to be useful for monitoring the course of polyneuropathy in clinical trials.

Peripheral somatic nerve function in relation to glucose tolerance in an elderly caucasian population: The Hoorn study

Only sparse and contradictory data are available on peripheral somatic nerve function in relation to the total range of glucose tolerance. A random sample (n = 708) of people, stratified by age, sex, and glucose tolerance, from a Caucasian population aged 50 to 74 years was invited to undergo an examination including measures of large‐fibre nerve function (ankle and knee reflexes, vibration sense, vibratory perception threshold (VPT) at the foot) and one measure of small‐fibre function (thermal discrimination threshold (TDT) at the foot). A total of 267 subjects with a normal glucose tolerance (NGT), 167 with impaired glucose tolerance (IGT), 90 with newly diagnosed diabetes mellitus (NDM), and 73 with previously known diabetes (KDM) were included. KDM was associated with the highest prevalence of large‐fibre nerve dysfunction. Within the range from NGT to NDM, most large‐fibre function measures showed a decline with decreasing glucose tolerance. The TDT showed a decrease with an increase in fasting and post‐load insulin levels (p < 0.05). We conclude that glucose intolerance is associated with impaired peripheral large‐fibre nerve function, an association which seems to apply even in the non‐diabetic range. Higher insulin levels were associated with a better small‐fibre nerve function.

Complaints of neuropathy related to the clinical and neurophysiological assessment of nerve function in patients with diabetes mellitus

To determine the value of a detailed evaluation of neuropathic sensory complaints in assessing diabetic polyneuropathy, a questionnaire listing different sensory symptoms was compared with a clinical and neurophysiological examination of the peripheral nerves. Thirty-seven insulin dependent and thirty-one non-insulin dependent diabetic patients who were consecutively referred because of suspected polyneuropathy were investigated. In all patients both clinical and neurophysiological examination confirmed the diagnosis of polyneuropathy. Only the scores of the clinical examination were significantly correlated with the scores of the sensory symptoms (r = 0.31, P < 0.01). Using a factor analysis, a dimension of complaints of sensory alteration could be distinguished from a dimension of complaints of neuropathic pain (alpha coefficients 0.88 and 0.86, respectively). Tingling sensations turned out to be an expression of the dimension of complaints of sensory alteration. The scores of clinical and neurophysiological examinations were only significantly correlated with the dimension of sensory alteration (r = 0.38, P < 0.002; r = 0.37, P < 0.02, respectively). We conclude that only symptoms of numbness and tingling sensations in hand and feet are associated with objectively assessed diabetic polyneuropathy.

Quantitative sensory examination in diabetic children: Assessment of thermal discrimination

Vibration perception thresholds (VPTs) and thermal discrimination thresholds (TDTs) were investigated in 55 insulin‐dependent diabetic children aged 11.3 ± 3.9 years (mean ± SD) and in 81 controls. There was no significant difference in VPTs between the two groups. TDTs were significantly higher in the group of diabetic children (p<0.03). Eight diabetic children had abnormal thermal sensation and one child had abnormal vibratory sensation. TDT correlated positively with duration of diabetes mellitus (r = 0.25; p<0.05). Both investigations can be carried out easily and are unobtrusive, which is an important advantage in the examination of children.

Hyperhomocysteinaemia is not related to risk of distal somatic polyneuropathy: The Hoorn Study

Abstract. Hoogeveen EK, Kostense PJ, Valk GD, Bertelsmann FW, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CDA (University Hospital Vrije Universiteit, Amsterdam). Hyperhomocysteinaemia is not related to risk of distal somatic polyneuropathy: The Hoorn Study. J Intern Med 1999; 246: 561–566.

Cold and Warm Cutaneous Sensation in Diabetic Patients

The assessment of cutaneous thresholds for thermal sensation is now recognized as a valuable method to detect small nerve fibre function in diabetes. Methods commonly used do not allow separate measurements of warm and cold perception. However, there is evidence that the fibre subtypes which signal cold and warm sensation are different (A‐delta‐fibres and C‐fibres, respectively). To investigate if diabetes affects cold and warm sensation equally, thresholds were assessed separately in 30 diabetic patients (age 47.9 ± 15.1 (± SD) years; duration of diabetes, 19.1 ± 13.3 years). Comparisons were made with 71 non‐diabetic control subjects (age 59.7 ± 22.1 years). Thermal discrimination thresholds for cold and warm sensation were determined for the left foot with a two‐alternative forced choice method. In both diabetic patients and in the control group cooling thresholds were smaller than warming thresholds. In diabetic patients log thermal discrimination thresholds for warmth increased 0.1 per decade (p < 0.001), a relationship comparable to that seen in non‐diabetic patients. There was no relationship between cooling thresholds and age in diabetic patients despite a significant (p < 0.001) deterioration with age in control subjects. This difference in the influence of age on cold sensitivity was significant (p < 0.03). Both warm and cold sensation were not related to the duration of diabetes. We conclude that assessment of warm threshold is preferred for the detection of minor disturbances of small nerve fibre function in diabetes.