Diabetic Neuropathy Study Research Articles

Multicenter study of diabetic autonomic neuropathy with power spectrum analysis of heart rate variability

Multicenter study of diabetic autonomic neuropathy with power spectrum analysis of heart rate variability

The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study.

The magnitude of the health problem from diabetic neuropathies remains inadequately estimated due to the lack of prospective population-based studies employing standardized and validated assessments of the type and stage of neuropathy as compared with background frequency. All Rochester, Minnesota, residents with diabetes mellitus on January 1, 1986, were invited to participate in a cross-sectional and longitudinal study of diabetic neuropathies (and also of other microvascular and macrovascular complications). Of 64,573 inhabitants on January 1, 1986 in Rochester, 870 (1.3%) had clinically recognized diabetes mellitus (National Diabetes Data Group criteria), of whom 380 were enrolled in the Rochester Diabetic Neuropathy Study. Of these, 102 (26.8%) had insulin-dependent diabetes mellitus (IDDM), and 278 (73.2%) had non-insulin-dependent diabetes mellitus (NIDDM). Approximately 10% of diabetic patients had neurologic deficits attributable to nondiabetic causes. Sixty-six percent of IDDM patients had some form of neuropathy; the frequencies of individual types were as follows: polyneuropathy, 54%; carpal tunnel syndrome, asymptomatic, 22%, and symptomatic, 11%; visceral autonomic neuropathy, 7%, and other varieties, 3%. Among NIDDM patients, 59% had various neuropathies; the individual percentages were 45%, 29%, 6%, 5%, and 3%. Symptomatic degrees of polyneuropathy occurred in only 15% of IDDM and 13% of NIDDM patients. The more severe stage of polyneuropathy, to the point that patients were unable to walk on their heels and also had distal sensory and autonomic deficits (stage 2b) occurred even less frequently--6% of IDDM and 1% of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-response bias in studies of diabetic complications: The rochester diabetic neuropathy study

Non-response can bias studies of disease conditions but its influence has rarely been evaluated due to limitations of available data on the non-respondents. Because of a detailed medical record review for eligibility, we were able to compare clinical as well as demographic characteristics of respondents and non-respondents in a population-based study of diabetic complications among Rochester, Minnesota residents. Non-respondents were older, less well educated, more likely to be widowed and more often retired. They were much more likely to have cardiovascular disease at baseline, but the prevalence of retinopathy, nephropathy and diabetic neuropathy was similar for respondents and non-respondents, who were also comparable with regard to type of diabetes and diabetic therapy. While these findings indicate that data from the Rochester Diabetic Neuropathy Study can probably be generalized to diabetic residents generally, they reemphasize the potential for non-response bias in epidemiologic studies of clinical conditions, especially cardiovascular disease.

Cyclandelate in diabetic neuropathy. A double-blind, placebo-controlled, randomized, cross-over study

Cyclandelate has the ability to improve the rheological properties of the blood and therefore may improve blood supply of peripheral nerves. Previous studies in diabetic neuropathy have shown beneficial effects of the drug. We performed a double-blind, placebo-controlled, cross-over study in 40 diabetic patients with cyclandelate in a dose of 1600 mg daily. Motor and sensory nerve conduction velocities, late responses, thermal discrimination thresholds, vibration perception thresholds and pain scores were studied. We were not able to show any positive effect of the drug and therefore conclude that cyclandelate is not effective in the treatment of diabetic neuropathy.

A Study of Peripheral Diabetic Neuropathy. The Application of Age‐Related Reference Values

The standardization of methodology and the provision of age-related reference values have been addressed for the design of and interpretation of data from a multicentre neuropathy trial. Age-related reference values were generated from 120 healthy volunteers. Vibration perception thresholds (VPT) deteriorated significantly with age (p less than 0.001). Patients were selected on the basis of age-related abnormal VPT and peroneal motor nerve conduction velocity. They were assessed at the beginning and end of a placebo run-in period (baseline data). The coefficients of variation (CV%) for VPT at the medial malleolus (16.81 per cent, n = 316) and great toe (19.23 per cent, n = 313) were lower compared to results in healthy volunteers (29.7 per cent and 20.8 per cent, respectively, n = 49). The CV% for expiratory:inspiratory (E:I) ratio (4.82 per cent, n = 215), Valsalva manoeuvre (10.84 per cent, n = 249) and 30:15 ratio (7.73 per cent, n = 292) from patients corresponded to those recorded in volunteers (7.6 per cent, n = 45 11.0 per cent, n = 49 9.5 per cent, n = 48, respectively). Most patient values for VPT at the great toe fell beyond the 95 centile line for volunteers. E:I ratio for volunteers showed a more variable relationship with age, although patient values appeared to be located below the 5 centile line for volunteer data.

The Rochester Diabetic Neuropathy Study

A cross-sectional survey and subsequent longitudinal study among diabetic residents of Rochester, MN--The Rochester Diabetic Neuropathy Study (RDNS)--is population-based and uses quantitative, validated, and unique end points to detect, classify, and stage neuropathy. Nondiabetic persons, drawn from the same population, serve as controls. For patients 10 to 70 years old, the RDNS cohort is representative of diabetics living in Rochester, MN. We assessed reproducibility of tests used to characterize and quantitate severity of neuropathy in 20 diabetic subjects without neuropathy and with varying severities of neuropathy. Using intraclass correlation coefficient (rI) as a measure of test reproducibility, we found high rI (usually 0.9 or better) with small confidence intervals for the Neurologic Disability Score (NDS); weakness subset of NDS (W-NDS); vibratory and cooling detection thresholds (using computer-assisted sensory examination [CASE] IV); compound muscle action potentials; sensory nerve action potentials; and motor nerve conduction velocities. There was good agreement among three trained observers for NDS and the W-NDS.

Correlation between vibratory detection threshold and conduction study of sural nerve in diabetic patients

Vibratory detection threshold (VDT) was determined on the plantar side of the distal phalanx of the right great toe of 22 diabetic (NIDDM) patients. In addition, a neurological examination and a sural nerve conduction study were performed. Peripheral neuropathy, based on our criteria, was found in 41% of the patients. VDT was abnormally high in 23% of the patients. The combined frequency of the abnormality of the amplitude of the action potential of the sural nerve or the conduction velocity or both was 73%. The nerve conduction study showed the highest sensitivity in detecting the abnormality of the peripheral nerve in this study; this is in agreement with the result shown in the literature. Seven patients showed no response to electrical stimulation of the sural nerve, although VDT was obtained in these patients. Among the 6 patients that underwent the normal sural nerve conduction study, no one showed abnormally high VDT. The determination of VDT seems to be a useful examination for the follow-up study of diabetic neuropathy, although it is less sensitive than the sural nerve conduction study.

Development of a method to determine autonomic nervous system function in the rat

A noninvasive method to evaluate autonomic nervous system (ANS) function in animals is needed for studies of diabetic autonomic neuropathy. These studies modified the RR-variation test, used to test diabetic ANS function in humans, and applied it to rats. Permanent wire electrodes were implanted in the chest wall of a rat. ECG complexes were obtained by connecting the electrodes to leads going to an impedence pneumograph and high gain coupler. This information was then converted into square waves by a trigger unit and recorded on magnetic tape for subsequent analysis by computer. Recordings were at least 60 seconds long, of which 30 seconds was used for analysis. In order to establish autonomic influence, RR-variation was measured before and after application of pharmacologic agents. Directly decreasing parasympathetic tone with atropine (20 mg/kg, n = 6) increased heart rate ( P < 0.001) and decreased RR-variation ( P < 0.05). Directly decreasing beta adrenergic tone with propranolol (10 mg/kg, n = 7) decreased heart rate ( P < 0.01) but had no effect on RR-variation (NS). Stimulation of the beta adrenergic receptors (isoproterenol, 0.1 mg/kg, n = 5) increased heart rate ( P < 0.01) but decreased RR-variation ( P < 0.01). Increasing parasympathetic tone reflexly with alpha-1 adrenergic receptor stimulation (phenylephrine, 1 mg/kg, n = 7) decreased heart rate ( P < 0.05) and increased RR-variation ( P < 0.025). The responses to phenylephrine could be blocked by parasympathetic blockade. Phentolamine (0.1 mg/kg, n = 7) caused an increase in heart rate ( P < 0.001) and a decrease in RR-variation ( P < 0.01). The responses to phentolamine could be blocked by beta adrenergic receptor blockade. These results show that changes in RR-variation are due to both direct and reflex changes of ANS activity. Since propranolol had no effect on RR-variation, we conclude that during nonstressed situations RR-variation represents predominantly parasympathetic activity. However, stress (isoproterenol infusions) and blood pressure changes can alter RR-variation. Thus, RR-variation appears to be a reliable noninvasive index of autonomic activity in rats and could be used in animal studies of diabetic autonomic neuropathy.

A Follow-up Study of Painful Diabetic Neuropathy

A Follow-up Study of Painful Diabetic Neuropathy

Dermal nerves in human diabetic subjects.

The lack of a nerve tissue source that is easily, safely, and repeatedly available has been a major impediment to the study of human diabetic neuropathy. In this study dermal nerves from skin, obtained at biopsy and autopsy from the lower leg and at autopsy from the mid-abdomen, were subjected to quantitative electron microscopy to assess for diabetic perineurial cell basement membrane thickening, a change previously reported in sural nerve. A highly significant degree of perineurial cell basement membrane thickening was found in the diabetic subjects. Other structures in dermal nerves, such as axons, myelin, Schwann cells, and their organelles are also amenable to quantitative ultrastructural study. Skin biopsy is a way to obtain samples of peripheral nervous system tissue safely and repeatedly for the study of diabetic neuropathy.

Genetic and metabolic studies in diabetic neuropathy

Forty-one diabetic patients with symptomatic diabetic neuropathy were studied together with an equal number of matched diabetic subjects without neuropathy. The acetylator status was determined and HLA-A, B, C and DR antigens were investigated. Metabolic control was assessed by measurement of glycosylated haemoglobin and by the mean of multiple random clinic blood glucose values. No significant difference was observed between the two groups in the proportion of fast and slow acetylators. The distribution of HLA frequencies was similar in subjects with and without neuropathy for both Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients. When compared with diabetic subjects without neuropathy, the neuropathy group had higher levels of both glycosylated haemoglobin (mean +/- SEM: 50.1 +/- 1.4 versus 57.5 +/- 1.8 mmol hydroxymethylfurfural/mol haemoglobin (10.5 +/- 0.3 versus 12.0 +/- 0.4% haemoglobin A1, p less than 0.01) mean blood glucose (9.3 +/- 0.4 versus 11.3 +/- 0.5 mmol/l, p less than 0.005). This study provides no evidence that genetic factors increase the susceptibility of diabetic patients to develop neuropathy. In contrast, the elevated glycosylated haemoglobin and blood glucose levels strengthen the association between hyperglycaemia and diabetic neuropathy.

A follow-up study of painful diabetic neuropathy: physical and psychological aspects.

Twenty-one patients with painful diabetic neuropathy were followed up for about 18 months by means of physical and psychological tests. Patients with painful diabetic neuropathy had significantly more neurotic, anxious and depressive traits than those with non-painful diabetic neuropathy. During the course of the study, 17 patients out of 21 were found to be relieved of their neuropathic symptoms with improved blood glucose control and medications. However, despite this improvement, diabetic retinopathy and nephropathy of the patients deteriorated. Patients with improved neuropathy had gained body weight, with a concomitant relief of depression, nervous tendency and anxiety. However, lack of extroversion was not changed at all. Patients with painful diabetic neuropathy were significantly less extroversive than those with non-painful diabetic neuropathy, even when their neuropathic symptoms might have improved. This study shows that although nervousness, anxiety and depressive tendencies may be secondary to the symptoms of painful diabetic neuropathy, lack of extroversion can be a primary characteristic trait which may easily induce painful diabetic neuropathy.

Peripheral neuropathy in mutant diabetic mouse [C57BL/Ks (db/db)

A new animal model for the study of diabetic neuropathy is presented. The homozygote (db/db) of the mouse strain C57BL/Ks shows severe diabetes with longstanding hyperglycemia. Electrophysiological studies showed severely decreased motor nerve conduction velocity. Morphometric examination of sensory and motor nerves at different levels revealed absence of large myelinated fibers, with morphological features indicative of axonal atrophy.

Nerve biopsy and conduction studies in diabetic neuropathy.

Morphological findings in sural nerves were related to nerve conduction in 12 patients with diabetic neuropathy, five with mainly sensory involvement, four with severe, symmetrical sensory-motor polyneuropathy, and three with multiple mononeuropathy. All had loss of large and small myelinated and of unmyelinated fibres, even early in the disease; segmental remyelination was the most prominent myelin alteration in teased fibres, segmental demyelination was found in only a few fibres. Axonal degeneration and Schwann cell damage seem to proceed independently of each other. The relation between recorded conduction velocity and that expected from the diameter of the largest fibres indicated that slowing of 20 to 30% was due to causes other than fibre loss; a grossly diminished conduction velocity was caused mainly by fibre loss. Electrophysiological findings in the sural nerve were largely representative of findings in other nerves, though abnormalities were less marked in the median nerve. In half the endoneurial vessels from diabetic neuropathy the perivascular space was thickened or contained more layers of basal laminae than normal. The same abnormalities were found in one-quarter of the endoneurial vessels from other acquired neuropathies.

Clinical and histological studies in diabetic neuropathy

Sural nerve biopsy was performed in twenty-four diabetic patients, with clinical and electrophysiological evidence of diabetic neuropathy. Material from an autopsy case was also examined. Vessels plugged with fibrin were seen within nerve in nine cases. In three cases fibrin was observed tracking into the vessel wall and in four, older thrombus was observed in vessels. Areas of necrosis in nerve bundles were seen in two of the latter. In two patients there had been a preceding episode of intravascular coagulation. Fibrin deposition within small vessels could well play a part in damaging the diabetic nerve and a disturbance of the balance between deposition and removal by fibrinolysis could explain phasic variation in the symptoms of neuropathy.

Recent Contributions to the Study of Diabetic Angiopathy and Neuropathy

Publisher Summary This chapter discusses the recent contributions to the study of diabetic angiopathy and neuropathy. Diabetes mellitus is a common disease in all parts of the world, but the clinical picture is different according to the economic and social conditions prevailing. In those parts where modern medical facilities are not easily attainable by everybody, diabetes mellitus often appears as pre-Banting-and-Best-diabetes. Many juvenile diabetics die in the course of one or two years without the disease being correctly diagnosed or properly treated and controlled. In countries with highly developed medicosocial organizations and widespread insurance systems, most diabetics—severe as well as mild— survive for many years. The diabetic population is characterized by the high incidence of incapacitating and life-threatening vascular abnormalities as well as of disturbances of central and peripheral nervous function, and here the problem is the lack of efficient means of preventing or treating these conditions. The most striking fact about diabetic microangiopathy is its relation to the duration of diabetes.

Electrophysiological studies in diabetic neuropathy.

In 30 patients with diabetic neuropathy sensory potentials in the median nerve, motor conduction in the lateral popliteal and median nerves, and electromyographic findings in distal and proximal muscles were compared with the severity of symptoms and signs. All patients had abnormalities in at least one of the electrophysiological parameters. The sensory potentials were the most sensitive indicator of subclinical involvement; abnormalities were found in 24 patients, 12 of whom had no sensory symptoms or signs and five of whom had no other clinical or electrophysiological evidence of neuropathy in the upper extremities. This indicates that sensory nerve fibres may be affected before motor. The next most sensitive parameter was the presence of fibrillation potentials, found in more than half the distal muscles examined. Slowing in motor conduction in the lateral popliteal nerve was the only electrophysiological change correlated to the severity of the neuropathy, and no other electrophysiological parameter was correlated to the duration or the severity of the neuropathy or the diabetes. An onset of neuropathy before or simultaneously with the manifestations of the diabetes, as well as the frequent occurrence of asymptomatic changes in sensory conduction, support the evidence at hand that the neuropathy develops concomitantly with and as an integral part of the metabolic disturbance rather than as a consequence of the vascular complications of diabetes. Of three patients with clinical signs or symptoms of a diabetic amyotrophy, two had asymptomatic electrophysiological abnormalities in distal nerves and muscles, consistent with widespread involvement of the peripheral nerves. The third patient had electromyographic changes in the medial vastus muscles suggestive of a myopathy. Motor and sensory conduction in distal and proximal nerves were normal.