Endoneurial localisation of microvascular damage in human diabetic neuropathy

Summary Twenty diabetic patients with neuropathy underwent clinical and neurophysiological evaluation together with a detailed morphometric assessment of capillary pathology in endoneurial and epineurial microvascular beds of the sural nerve. Morphological data were compared with ten non-diabetic control subjects. There were no significant differences in control subjects between basement membrane area, endothelial cell area, endothelial cell profile number or luminal area of endoneurial when compared with epineurial capillaries. In contrast, when compared with epineurial capillaries, endoneurial capillaries from diabetic patients demonstrated a significant increase in basement membrane (p<0.001) and endothelial cell (p<0.001) area and a significant reduction in luminal area (p<0.001). There was no significant difference in endothelial cell profile number between endoneurial and epineurial capillaries amongst diabetic patients. Previous studies have demonstrated a good correlation between the degree of microangiopathy and measures of neuropathic severity. In the present study increased endoneurial capillary basement membrane area was significantly related to reduced peroneal nerve conduction velocity (p<0.001), myelinated fibre density (p<0.001) and elevated vibration (p<0.05) and thermal (p<0.001) perception. Increased endothelial cell area and reduced luminal size were related to a reduced peroneal nerve conduction (p<0.05, p<0.01, respectively), reduced myelinated fibre density (p<0.05, p<0.01) and elevated thermal perception (p<0.05, p<0.001). Epineurial capillary basement membrane, endothelial cell and luminal area failed to relate to measures of neuropathic severity. This study has demonstrated more advanced microangiopathy and a more significant relationship to neuropathic severity in endoneurial compared with epineurial capillaries, thus providing further support for the role of microangiopathy in the pathogenesis of human diabetic neuropathy.     

Impaired blood flow and arterio-venous shunting in human diabetic neuropathy: a novel technique of nerve photography and fluorescein angiography

Summary New techniques of sural nerve photography and fluorescein angiography which are able to provide an index of nerve blood flow have been developed. Under local anaesthetic, 3 cm of sural nerve was exposed at the ankle using an operating microscope. Without disturbing the epineurium, vessels were identified and photographed at a standard magnification (× 30). These were independently graded by an ophthalmologist not otherwise involved with the study. Fluorescein angiography was then carried out on the exposed nerve. The fluorescein appearance time and intensity of fluorescence were quantified, using computer analysis of digitised images. Thirteen subjects with chronic sensory motor neuropathy, five non-neuropathic diabetic and nine normal control subjects were studied. The mean epineurial vessel pathology score of the neuropathic group was significantly higher than the combined normal control and non-neuropathic diabetic groups (p <0.01). Direct epineurial arteriovenous shunting was observed in six neuropathic and one non-neuropathic diabetic patients and not in any of the normal control subjects. The nerve fluorescein appearance time was significantly delayed in subjects with chronic sensory motor neuropathy (51.5 ± 12 s) compared to both normal (34.7 ± 9 s, p <0.01) and non-neuropathic diabetic subjects (33.4 ± 11 s, p <0.025). The mean intensity of fluorescence at 96, 252 and 576 s, was significantly lower in subjects with chronic sensory motor neuropathy compared with both of the other groups (p <0.05). The epineurial vessel pathology score was significantly related to reduced sural (p <0.01) and peroneal (p <0.001) nerve conduction velocities, elevated vibration (p <0.01) and thermal (p <0.001) perception and the severity of retinopathy (p <0.002). The fluorescein appearance time was significantly related to reduced sural sensory (p <0.02) conduction velocity, elevated vibration (p <0.01) perception and epineurial vessel (p <0.002) pathology score, but it failed to relate to peroneal motor (p = 0.06) conduction velocity, thermal (p = 0.1) perception and the severity of retinopathy (p = 0.3). Intensity of fluorescence was significantly related to fluorescein appearance time (at 96 s, p <0.001; at 576 s, p <0.05) but did not relate to measures of neuropathic severity. These techniques have enabled us to observe that epineurial vessel anatomy is abnormal and that nerve blood flow is impaired in subjects with chronic sensory motor neuropathy. In addition epineurial arterio-venous shunting may be a feature of diabetic neuropathy. These techniques may further be applied to study nerve blood flow in early diabetic neuropathy.     

Parotid salivary secretion in diabetic autonomic neuropathy

Parotid salivary flow rates and amylase concentrations were measured in three groups of eight subjects each (normal control, non-neuropathic diabetic, and neuropathic diabetic). Flow rates were significantly reduced in neuropathic diabetic patients as compared with normal controls (p < 0.001) and non-neuropathic diabetic patients (p < 0.02). Amylase concentrations were similar. These data are consistent with parasympathetic denervation of the parotid gland in diabetic neuropathy and provide evidence for a widespread distribution of autonomic denervation in diabetes.     

Exercise-induced conduction velocity increment: a marker of impaired peripheral nerve blood flow in diabetic neuropathy

Summary Severe microvascular disease exists at the stage of clinical diabetic neuropathy. A non-invasive test that will identify those diabetic subjects who will eventually develop neuropathy is essential for early intervention. Sural sensory conduction velocity was recorded (x 3) in 12 non-neuropathic diabetic subjects, 15 diabetic subjects with established neuropathy and 16 age-matched normal control subjects, before and after exercise to 80% age/sex predicted maximum heart rate. Fixed sural electrodes were used. Subcutaneous temperature was recorded by a needle thermocouple placed near the sural nerve. Sural sensory conduction velocity increased significantly after exercise in normal subjects (p<0.01, mean increase 5.07 m/s) and non-neuropathic diabetic subjects (p<0.02, mean increase 3.99 m/s) but not in neuropathic subjects (mean increase 0.99 m/s). Subcutaneous temperature rose significantly in normal subjects (p<0.01, mean increase 2.07°C) and non-neuropathic diabetic subjects (p<0.001, mean increase 2.52 °C) but not in neuropathic subjects (mean increase 0.15 °C). However, sural sensory conduction velocity increased by 1.2 m · s^–1. °C^–1 following direct warming of the limb in six neuropathic subjects which was comparable to that of normal and non-neuropathic subjects (1.49 and 1.48 m · s^–1. °C^–1). The impairment of exercise conduction increment in diabetic neuropathy suggests impaired nerve blood flow in diabetic neuropathy.     

NO-dependent Smooth Muscle Vasodilatation is Reduced in NIDDM Patients with Peripheral Sensory Neuropathy

In order to determine the involvement of denervation in endothelium-independent, nitric oxide (NO)-dependent smooth muscle vasodilatation, we have measured vascular endothelial and smooth muscle function in three groups of age- and sex-matched patients: 8 patients with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) with neuropathy; 7 NIDDM patients without neuropathy; and 10 non-diabetic control subjects. Laser Doppler probes were used to measure blood flow in the dorsum of the left foot. Vascular endothelial response was assessed by measuring vasodilatory responses to iontophoretic application of acetylcholine to the dorsum of the foot. Vascular smooth muscle activity was assessed by the response to iontophoresis of sodium nitroprusside (SNP)—a NO donor and direct vasodilator. The vasodilator response to acetylcholine, expressed as the ratio of peak to basal blood flow, was significantly reduced in both diabetic groups when compared to non-diabetic controls (geometric mean ×/÷ anti-logged SD 9.81 ×/÷ 1.65 versus patients with neuropathy 3.50 ×/÷ 2.03, p < 0.005 and diabetic non-neuropathic subjects 3.49 ×/÷ 1.67, p < 0.005). The difference between the two groups of diabetic patients was not significant. In contrast, the vasodilatation to nitroprusside was significantly reduced only in the diabetic neuropathic patients, significantly lower than in either the non-neuropathic diabetic controls or the non-diabetic controls (2.1 ×/÷ 2.0 versus 6.42 ×/÷ 1.56 and 7.02 ×/÷ 2.05, p < 0.005). This indicates that neuropathy is important in abnormalities of endothelium-independent vasodilatation. © 1997 by John Wiley & Sons, Ltd.     

Sural nerve pathology in diabetic patients with minimal but progressive neuropathy

Aims/hypothesis The early pathological features of human diabetic neuropathy are not clearly defined. Therefore we quantified nerve fibre and microvascular pathology in sural nerve biopsies from diabetic patients with minimal neuropathy.Methods Twelve diabetic patients underwent detailed assessment of neuropathy and fascicular sural nerve biopsy at baseline, with repeat assessment of neuropathy 8.7±0.6 years later.Results At baseline, neuropathic symptoms, neurological deficits, quantitative sensory testing, cardiac autonomic function and peripheral nerve electrophysiology showed minimal abnormality, which deteriorated at follow-up. Myelinated fibre density, fibre and axonal area, and g-ratio were normal but teased fibre studies showed paranodal abnormalities (p<0.001), segmental demyelination (p<0.01) and remyelination (p<0.01) without axonal degeneration. Unassociated Schwann cell profile density (p<0.04) and unmyelinated axon density (p<0.001) were increased and axon diameter was decreased (p<0.007). Endoneurial capillaries demonstrated basement membrane thickening (p<0.006), endothelial cell hyperplasia (p<0.004) and a reduction in luminal area (p<0.007).Conclusions/interpretation The early pathological features of human diabetic neuropathy include an abnormality of the myelinated fibre Schwann cell and unmyelinated fibre degeneration with regeneration. These changes are accompanied by a significant endoneurial microangiopathy.     

Selective neuropathy and preserved vascular responses in the diabetic Charcot foot

Summary Charcot arthropathy is a disabling complication of diabetic neuropathy. It is however, unclear why it occurs in only a small number of neuropathic patients. We have studied 12 diabetic patients (10 insulin-dependent) with an acute Charcot arthropathy, and compared their neuropathy and vascular responsiveness with 12 diabetic patients (10 insulin-dependent) with recurrent neuropathic foot ulceration, 12 diabetic control subjects (9 insulin-dependent) and 10 normal non-diabetic subjects. The Charcot arthropathy patients demonstrated a preservation of warm perception, 6 (5.5) °C, but complete loss of peripheral cold perception, 10 (0) °C, p<0.001 (median (interquartile range)). This contrasted with the ulcerated neuropathy patients, who had equally severe impairment of both warm and cold sensory thresholds, 10 (0.5) °C vs 10 (1) °C, respectively, the diabetic control subjects who were able to detect a 2 (1.3) °C warm stimulus and 3 (3.5) °C cold stimulus and the normal subjects, whose warm threshold was 2 (1) °C and cold was 2 (1) °C. Light touch perception at the foot was preserved in the Charcot patients 4 (4) g vs 100 (50) g, p<0.0002, in the ulcerated neuropathy patients. Vibration perception at the great toe and cardiovascular autonomic function tests (heart rate variability, Valsalva ratio and postural systolic blood pressure fall) were abnormal in both the Charcot patients and ulcerated neuropathy group, with no differences seen between the two groups. Peak skin blood flow at the great toe in response to local heating was preserved in the Charcot arthropathy patients, 63.36 (28.72) flow units when compared to the diabetic and normal subjects, 62.72 (47) flow units and 76.3 (33.92) flow units, respectively and much greater than in the ulcerated neuropathy patients 28.94 (37.39) flow units, p<0.0002. The diabetic patients developing Charcot arthropathy thus have a neuropathy and vascular responsiveness which distinguishes them from diabetic subjects developing neuropathic ulceration. This may be important in the pathogenesis of the Charcot foot.     

Advanced glycation endproducts in peripheral nerve in type 2 diabetes with neuropathy

Abstract Advanced glycation endproducts (AGE) accumulate over proteins as a consequence of diabetic hyperglycemia, and thus contribute to the pathogenesis of diabetic complications. To improve the understanding of the pathology of diabetic neuropathy, AGE accumulation was analyzed in sural and/or femoral nerves obtained under spinal anesthesia from 8 type 2 diabetic patients with both distal symmetrical polyneuropathy and proximal neuropathy. Pronounced AGE immunoreactivity was detected on axons and myelin sheaths in 90% of diabetic peripheral nerves but not in the control specimen. The intensity of axonal AGE immunopositivity significantly correlated with the severity of morphological alterations (p<0.005). AGE localization, demonstrated by immunohistochemical methods, was also present in the endoneurium, perineurium and microvessels. Morphometric analysis of the diabetic peripheral nerve showed perineurial thickening (diabetic vs. control, 15.5±4.9 vs. 6.6±2.1 µm, p<0.001), narrowing of the microvessel lumina (66.6±50.5 vs. 579.5±38.4 x10³ µm², p<0.001) and significant reduction in the number of preserved axons (3.6±3 vs. 8.9±2.3 per 10⁵ µm² per area, p<0.037). The sera of diabetic patients contained epitope(s) of AGE structure and soluble immune complexes containing AGE moiety. In conclusion, to the best of our knowledge, this is the first study providing evidence for excessive AGE formation on peripheral nerve components, primarily axons, and a significantly higher level of circulating AGE-immune complexes in patients with both distal diabetic polyneuropathy and proximal neuropathy. Humoral immune mechanisms, including the production of anti-AGE autoantibody, may potentially be involved in the development of structural abnormalities described in this report.     

Direct measurement of capillary blood flow in the diabetic neuropathic foot

Summary The two major components of the microcirculation in the diabetic neuropathic foot have been examined in detail. Nutritive capillary blood flow was measured directly using the non-invasive technique of television microscopy, applied to the toe nailfold. Arteriovenous shunt flow was assessed using the technique of laser Doppler flowmetry, applied to the toe pulp. Fourteen diabetic patients with peripheral and autonomic neuropathy, 11 with no clinical evidence of neuropathy and 14 normal subjects were studied. Laser Doppler flowmetry (predominantly arteriovenous shunt flow) was increased more than three-fold (p<0.01) in the diabetic patients with neuropathy compared to control subjects, (median 3.57, interquartile range 2.00–5.32 volts vs median 0.93, interquartile range 0.47–2.36 volts respectively). There was no evidence of skin capillary closure. The calculated capillary blood flow (erythrocyte flux) was significantly increased in the diabetic neuropathic patients compared to control subjects (median 76.4, interquartile range 34.4–109.8 picolitres/s vs median 23.2, range 8.0–44.8 picolitres/s, p<0.01). This study demonstrates that foot skin capillary blood flow is increased in diabetic patients with neuropathy. There is, therefore, no evidence to support the supposition that capillary ischaemia, either secondary to a capillary steal phenomenon or advanced microangiopathy, is a feature of diabetic neuropathy under resting conditions.     

Muscular atrophy in diabetic neuropathy: a stereological magnetic resonance imaging study

Summary Diabetic patients with polyneuropathy develop motor dysfunction. To establish whether motor dysfunction is associated with muscular atrophy the ankle dorsal and plantar flexors of the non-dominant leg were evaluated with magnetic resonance imaging in 8 patients with symptomatic neuropathy, in 8 non-neuropathic patients and in 16 individually matched control subjects. In the neuropathic patients the muscle strength of the ankle dorsal and plantar flexors was reduced by 41 % as compared to the non-neuropathic patients (p < 0.005). Volume of the ankle dorsal and plantar flexors was estimated with stereological techniques from consecutive cross-sectional images of the lower leg. The neuropathic patients had a 32 % reduction in volume as compared with the non-neuropathic patients (p < 0.005). To determine the regional distribution of atrophy cross-sectional magnetic resonance images were performed at predetermined levels of the lower leg in relation to bone landmarks. In the neuropathic patients there was an insignificant increase of 3 % of muscle area at the proximal lower leg level, whereas the atrophy was 43 % (p < 0.002) at the mid lower leg level and 65 % (p < 0.002) distally. Analysis of individual muscles confirmed that the atrophy predominated distally. We conclude that muscular atrophy underlies motor weakness at the ankle in diabetic patients with polyneuropathy and that the atrophy is most pronounced in distal muscles of the lower leg indicating that a length dependent neuropathic process explains the motor dysfunction. [Diabetologia (1997) 40: 1062–1069] Received: 17 January 1997 and in revised form: 24 April 1997     

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.     

Abnormal Digital Pressure Measurements in Diabetic Neuropathic Foot Ulceration

The diabetic neuropathic ulcer is typically slow to heal and recurrent. Macrovascular insufficiency is usually excluded as foot pulses are present and ankle:brachial pressure ratios are not decreased. These assessments cannot however exclude more distal vascular disease. Digital pressure measurements enable a reliable assessment of the distal peripheral vascular status to be made. The aim of this study was therefore to use toe pressures to assess the contribution of distal ischaemia in the pathogenesis of the neuropathic ulcer. Sixteen diabetic patients with recurrent neuropathic foot ulceration had their toe pressures compared to 10 neuropathic patients without a history of foot ulceration, 10 diabetic control subjects, and 11 normal subjects. Four non-diabetic patients with neuropathy and foot ulceration were also assessed. All subjects had ankle:brachial pressure indices ≧ 1. Toe pressure was assessed using laser Doppler flowmetry to record the return of skin blood flow. The toe:brachial pressure index (TBI) was then calculated. The diabetic patients with a history of recurrent neuropathic ulceration, had the lowest mean TBI, 0.63 ± 0.14 (SD), compared to the non-ulcerated diabetic neuropathy patients, the diabetic control subjects, and the normal subjects. 0.84 ± 0.11, 0.82 ± 0.1, and 0.81 ± 0.07, p < 0.01, respectively. Three of the four non-diabetic patients with neuropathic foot ulceration also had an abnormally low TBI. Reduced toe pressure measurements are thus found to be associated with neuropathic foot ulceration. The contribution of distal ischaemia in the pathogenesis of the diabetic neuropathic foot ulcer needs to be evaluated. One hundred and eight non-insulin-dependent diabetic patients who had been tested for autonomic dysfunction in 1984/85 were re-evaluated 5 years later. Autonomic function was assessed by means of four cardiovascular tests (heart rate variation during deep breathing and standing, and blood pressure variation after standing and sustained handgrip). Eighteen subjects were lost to follow-up; in the 90 patients who completed the study, both the deep breathing and the handgrip test significantly worsened (respectively from 13.7 ± 7.8 to 11.6 ± 6.3 beats min^?1 p < 0.01, and from 16.9 ± 8.2 to 12.7 ± 7.1 mmHg, p < 0.001), whereas both the 30:15 ratio and the variation of blood pressure on standing did not change. The impairment of a comprehensive evaluation score (from 2.5 ± 1.7 to 3.0 ± 1.5; p < 0.05) also confirmed the gradual deterioration of autonomic function over the study period.     

Soluble leucocyte adhesion molecules in diabetic retinopathy stimulate retinal capillary endothelial cell migration

Summary Diabetic retinal neovascularisation is considered to be a consequence of retinal ischaemia caused by capillary occlusion. Capillary occlusion is the result of microvascular thrombi in which erythrocytes, platelets and leucocytes each may play a role. We investigated the role of leucocytes in this process and the subsequent angiogenic response. We studied the serum levels of the soluble leucocyte adhesion molecules soluble E-Selectin, soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) in the serum of 93 patients with insulin-dependent diabetes (IDDM) and varying degrees of retinopathy and 47 healthy age and sex matched control subjects. We also measured the ability of serum to stimulate retinal capillary endothelial cell migration using an assay of angiogenesis in vitro. Soluble E-Selectin and sVCAM-1 levels were raised in all patients with IDDM (p < 0.001; p < 0.001) particularly those with retinopathy (p < 0.001; p < 0.001). Soluble E-Selectin levels were highest in the patients with severe non-proliferative diabetic retinopathy (p < 0.001) and sVCAM-1 levels were highest in patients with proliferative diabetic retinopathy (p < 0.01). In contrast soluble ICAM-1 levels were the same in patients and control subjects (p > 0.05). Soluble E-Selectin levels in diabetic patients were correlated with the level of glycated haemoglobin (p < 0.05). Retinal endothelial cell migration-inducing (ECMI) activity was increased in patients with IDDM (p < 0.01) in particular in those with retinopathy (p < 0.01). Furthermore, in vitro ECMI activity could be blocked by antibodies to sVCAM-1 and sE-Selectin. These data point to a functional role for leucocyte adhesion in the microvasculopathy of diabetic retinopathy and may have implications for the induction of retinal angiogenesis. [Diabetologia (1997) 40: 1166–1171] Received: 7 January 1997 and in revised form: 19 May 1997     

Sympathetic mediated vasomotion and skin capillary permeability in diabetic patients with peripheral neuropathy

AIMS/HYPOTHESIS: A loss of sympathetic function could lead to changes in capillary fluid filtration in diabetic patients. We investigated whether a decreased sympathetically mediated vasomotion in the skin in diabetic patients with peripheral neuropathy is associated with an abnormal capillary leakage. METHODS: Three matched groups were studied: 18 diabetic patients with documented peripheral neuropathy (DN), 18 diabetic patients without peripheral neuropathy (D), and 18 healthy control subjects (C). Sensory and motor nerve function of the distal extremities were assessed by standard neurography, and expressed in a sensory-motor nerve function score. Sympathetic vasomotion of the skin microcirculation was assessed by determining the power of blood flow variability in the low-frequency (0.02-0.14 Hz) band by spectral analysis of laser Doppler flowmetry at the median ankle. Skin capillary leakage was evaluated by sodium fluorescein videodensitometry at the same site of the foot. RESULTS: Sympathetically mediated vasomotion of the foot skin microcirculation was lower in diabetic patients with documented peripheral neuropathy compared with diabetic patients without peripheral neuropathy and control subjects (p<0.001). Capillary sodium fluorescein leakage was larger in 18 diabetic patients with documented peripheral neuropathy than in diabetic patients without peripheral neuropathy (p<0.02) and C (p<0.005). Multiple regression analysis disclosed that a reduced sympathetically mediated vasomotion, together with a lower sensory-motor nerve function score, independently contributed to the variance in sodium fluorescein leakage, for 30% (p<0.001) and 17% (p<0.01), respectively. CONCLUSIONS: A loss of sympathetic tone, apart from sensory-motor nerve dysfunction, seems to be a major determinant of an increased capillary permeability in diabetic patients with neuropathy.     

Hypoxic neuropathy: relevance to human diabetic neuropathy

Summary Clinical and neurophysiological studies were conducted in 47 patients with chronic obstructive airways disease and compared with 46 age-matched control subjects. Symptomatic neuropathy was reported in 13% and ankle jerks were absent in 45% of hypoxic patients. Peroneal and median nerve conduction velocities and median and sural sensory nerve amplitudes were significantly reduced in hypoxic patients (p<0.01). Six hypoxic patients underwent biopsy of the sural nerve, soleus muscle and overlying skin. Nerve glucose, sorbitol, fructose and myo-inositol concentrations were normal. Detailed light and electronrmicroscopy revealed both nerve fibre and microvascular pathology. Segmental demyelination (32%) and unmyelinated fibre degeneration were found to be prominent lesions. The sural nerve perineurium was thickened due to an increase in the number of perineurial lamellae and an increase in intraperineurial space. Basement membrane thickening was observed in capillaries of nerve, muscle and skin. Endothelial cell hyperplasia and hypertrophy were observed in nerve and muscle capillaries but not in skin capillaries. In conclusion, this study has provided neurological, neurophysiological and neuropathological evidence of a neuropathy in hypoxic patients with chronic obstructive airways disease. These findings may be of relevance to some aspects of the aetiology of human diabetic neuropathy.     

Disordered Mobility of Large Joints in Association with Neuropathy in Patients with Long-standing Insulin-dependent Diabetes Mellitus

Movement performance was studied in 29 long-term patients with insulin-dependent diabetes mellitus (IDDM) and 29 matched control subjects. Velocity, range of motion, reaction time, and strength of ankle dorsal and plantar flexion and knee extension were measured. The neuropathic condition was assessed from clinical examination, nerve conduction studies, and quantitative sensory examination, and summed to obtain a neuropathy rank-sum score. Reaction time for the diabetic patients was increased by 29 %, 23 %, and 22 % for ankle dorsal, ankle plantar, and knee extension movements respectively (p<0.001). Range of motion was slightly decreased at ankle dorsal flexion (12 %, p<0.05). There was an inverse relationship between range of motion and neuropathy rank-sum score for ankle dorsal (r = −0.68, p<0.001) and plantar flexion (r = −0.61, p<0.001). Peak velocity was significantly decreased at ankle dorsal (21 %, p<0.001) and plantar flexion (23 %, p<0.001) and was related to the isokinetic muscle strength. Peak velocity was also related to the neuropathy rank-sum score at ankle dorsal flexion (r = 0.57, p<0.002). We conclude that maximal movements at the ankle are delayed and slowed in long-term IDDM patients. The decreased peak velocity and the range of motion are related to the severity of neuropathy. © 1997 by John Wiley & Sons, Ltd.     

Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study

Summary The EURODIAB IDDM Complications Study involved the examination of 3250 randomly selected insulin-dependent diabetic patients, from 31 centres in 16 European countries. Part of the examination included an assessment of neurological function including neuropathic symptoms and physical signs, vibration perception threshold, tests of autonomic function and the prevalence of impotence. The prevalence of diabetic neuropathy across Europe was 28 % with no significant geographical differences. Significant correlations were observed between the presence of diabetic peripheral neuropathy with age (p < 0.05), duration of diabetes (p < 0.001), quality of metabolic control (p < 0.001), height (p < 0.01), the presence of background or proliferative diabetic retinopathy (p < 0.01), cigarette smoking (p < 0.001), high-density lipoprotein cholesterol (p < 0.001) and the presence of cardiovascular disease (p < 0.05), thus confirming previous associations. New associations have been identified from this study – namely with elevated diastolic blood pressure (p < 0.05), the presence of severe ketoacidosis (p < 0.001), an increase in the levels of fasting triglyceride (p < 0.001), and the presence of microalbuminuria (p < 0.01). All the data were adjusted for age, duration of diabetes and HbA_1c. Although alcohol intake correlated with absence of leg reflexes and autonomic dysfunction, there was no overall association of alcohol consumption and neuropathy. The reported problems of impotence were extremely variable between centres, suggesting many cultural and attitudinal differences in the collection of such information in different European countries. In conclusion, this study has identified previously known and new potential risk factors for the development of diabetic peripheral neuropathy. [Diabetologia (1996) 39: 1377–1384] Received: 14 December 1995 and in revised form: 27 June 1996     

The relation of protein C and protein S levels with cardiovascular risk in patients with diabetic neuropathy

BackgroundThis study was conducted to determine the clinically significance of protein C and protein S levels as a cardiovascular risk marker in patients with diabetic neuropathy.MethodsWe included 71 subjects. 50 of them were diabetics, 27 of them also had diabetic neuropathy(DN), 21 subjects were non diabetic. We evaluated these 3 group subjects’ protein C, protein S, fibrinogen, prothrombine time (PT), activated partial thromboplastine time (aPTT), total cholesterol, levels and Framingham Coronary Risk Score (FCRS).ResultsNon diabetic group’s protein C levels were higher than patients with DN (p < 0.05) and diabetic patients without DN (p < 0.05). But there were no difference in terms of protein C levels between patients with DN and diabetic patients without DN. FCRS of control group was lower than diabetic subjects(p < 0.01).ConclusionsWe found that protein C and S levels were much lower in diabetic patients than non diabetics.There was no difference between diabetic patients with DN and diabetic patients without DN in terms of protein C and protein S levels. Further, we couldn’t detect any finding that we can say protein C and Protein S levels can be used as a cardiovascular risk assessment marker in diabetic neuropathic patients.     

Relationship between myoinositol influx and lipids in diabetic neuropathy

Diabetic neuropathy is associated with abnormalities in lipid metabolism and has been postulated to be associated with abnormal myoinositol metabolism. Leucocyte myoinositol influx was measured using a triple isotope method in long-standing type 1 (insulin-dependent) diabetic patients with and without diabetic neuropathy and in a group of matched controls. No differences in fasting lipid, glucose concentrations or glycated haemoglobin were found in the diabetic groups. Myoinositol influx was significantly but negatively correlated with the serum very low density lipoprotein (VLDL) cholesterol concentration in patients with and without neuropathy but not in the controls. The VLDL cholesterol concentration also correlated negatively with the transporterK _m (R _s=–0.87,P<0.005, neuropathic group only) andV _max (R _s=–0.93,P<0.001, neuropathic group;R _s=–0.59,P<0.05, non-neuropathic group). Myoinositol influx correlated with the glycated haemoglobin only in the diabetic patients without neuropathy. The lipid relationships in diabetic subjects were independent of glucose control, which suggests that myoinositol influx mechanisms represent another transporter affected by intracellular lipid metabolism. The control of VLDL metabolism by fibrates could offer a method for reducing the progression of diabetic neuropathy.     

The steel ball-bearing test: a new test for evaluating protective sensation in the diabetic foot

Aims/hypothesis The aim of the study was to assess a new steel ball-bearing test as a means of evaluating protective sensation in the diabetic foot. Methods Subjects were enrolled for this study as follows: (1) 39 patients (mean age 61.3±9.7 years) with neuropathy and prior neuropathic ulcer (Group A); (2) 36 patients (mean age 63.7±10.1 years) with neuropathy without neuropathic ulcer (Group B); (3) 34 patients (mean age 52.1±10.4 years) without neuropathy (Group C); and (4) 21 healthy volunteers (mean age 46.7±8.7 years) (Group D). Neuropathy was diagnosed by means of neuropathy disability score (NDS). The plantar area over the second metatarsal head of each foot was examined with steel ball-bearings of varying diameters. The smallest diameter that the patient could feel was used to define the ball-bearing score (range 1–6). Results A high ball-bearing score was significantly more frequent in patients with neuropathic ulceration than in neuropathic patients without ulceration and in diabetic patients without neuropathy (p<0.001). A high score was also more frequent in neuropathic patients without ulceration, than in patients without neuropathy (p<0.001). The ball-bearing score was significantly (p=0.01) correlated with the NDS, the monofilament test, the vibration perception threshold and the thermal perception threshold. The ball-bearing test had a sensitivity of 84% and a specificity of 100% for impaired protective sensation due to neuropathy, and a sensitivity of 84.6% and a specificity of 86.1% for detection of patients with prior neuropathic ulceration. Conclusions/interpretation The steel ball-bearing test has a high sensitivity and specificity both for the evaluation of protective sensation and for detection of patients with prior neuropathic ulceration.