Increased sural nerve epineurial blood flow in human subjects with painful diabetic neuropathy

Aims/hypothesis The pathogenesis of painful diabetic neuropathy remains unknown. As a consequence we still do not have any effective, rational treatments and a greater understanding of the mechanisms is urgently required. Previous studies have shown no consistent morphological differences in the nerves of patients with and without painful neuropathy. The aim of this study was to compare epineurial haemodynamics in patients with chronic painful and painless neuropathy.Methods The techniques of microlightguide spectrophotometry and fluorescein angiography were used to measure epineurial intravascular oxygen saturation and blood flow respectively. Eleven patients with painful and eight with painless neuropathy were studied, with the groups matched carefully in terms of severity of neuropathy and diabetes control.Results Intravascular oxygen saturation was higher in the painful neuropathy group compared to those without pain (median 73.8% vs 67.7%, respectively; p=0.021). Fluorescein rise time was also faster in those with painful symptoms (median 18.3 s vs 53.6 s; p=0.046) indicating higher epineurial blood flow in these subjects.Conclusion/interpretation These results indicate that there are distinct differences in haemodynamics within the epineurium of the sural nerve in subjects with painful and painless neuropathy. Haemodynamic factors could therefore have an important role in the pathogenesis of neuropathic pain and might offer further insight into potential treatments for this distressing condition.Abbreviations DSP distal symmetrical polyneuropathy - FRT fluorescein rise time - HbO₂% intravascular oxygen saturation - NCV nerve conduction velocity - VPT vibration perception threshold     

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.     

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.     

The influence of local capsaicin treatment on small nerve fibre function and neurovascular control in symptomatic diabetic neuropathy

Topical treatment wit capsaicin cream has been shown to be successful in the treatment of different symptomatic nerve disorders like diabetic neuropathy. Conflicting data exist on the effect of capsaicin on nerve function and neurovascular control especially in patients with diabetic neuropathy. The aim of this pilot study was to investigate the impact of topical capsaicin application on small nerve fibre function and neurovascular control. Capsaicin cream was applied to the feet of 13 patients with symptomatc diabetic neuropathy over a period of 8 weeks. Before and during the treatment period, we investigated the total symptoms score, the vibration, thermal (heat and cold) and pain perception thresholds, and the neurovascular responses to heat and acetylcholine stimuli. In addition, the serum plasma levels of substance P, a neurotransmitter of nociceptor C-fibres, were measured. A significant improvement in total symptoms score was observed during topical capsaicin treament (18.3±3.2 vs. 14.3±3.3; p<0.05). An improvement in the heat perception threshold was also found (12.7±0.4°C vs. 11.4±0.7°C; p<0.05), while other sensory nerve fibre functions remained unchanged. No significant change in neurovascular control was observed, neither after mild thermal injury nor after stimulation with acetylcholine. Serum substance P levels increased after initiation of topical capsaicin treatment (72.9±5.8 pg/ml vs. 81.7±5.0 pg/ml; p<0.05), but returned to baseline levels during further treatment (77.4±8.3 pg/ml; n. s.). In conclusion, topical treatment with capsaicin cream over a period of 8 weeks in patients with symptomatic diabetic neuropathy is effective without adverse effects on nerve fibre function or neurovascular control. Received: July 2000 / Accepted in revised form: May 2001     

Functional and structural abnormalities in the nerves of Type I diabetic baboons: aminoguanidine treatment does not improve nerve function

Aims/hypothesis. To improve understanding of the pathophysiology of diabetic neuropathy and to establish a primate model for experimental studies, we examined nerve changes in baboons with Type I (insulin-dependent) diabetes mellitus. We also examined the effect of aminoguanidine (an inhibitor of the formation of advanced glycation end products) on nerve function.¶Methods. Male baboons (Papio hamadryas) were assigned to four groups; control, diabetic, control and diabetic treated with aminoguanidine. Diabetes was induced with streptozotocin (60 mg/kg, intravenous). Insulin and aminoguanidine (10 mg/kg) were injected subcutaneously daily. Motor and sensory nerve conduction velocity was measured using standard techniques. Autonomic function was examined by measuring heart rate response to positional change. Sural nerve morphometry was analysed in the diabetic group (mean duration 5.5 years) along with their age-matched controls.¶Results. The diabetic groups were smaller in size with a mean HbA_{1 c} of 8.9 ± 1.2 %. The nerve conduction velocity and heart rate response was reduced in the diabetic groups. Morphometric analysis of the diabetic sural nerve showed smaller axon diameter (2.99 ± 0.06 μm vs 3.29 ± 0.06 μm; p < 0.01) accompanied by thinner myelin (1.02 ± 0.02 μm vs 1.15 ± 0.02 μm, p < 0.01) with no change in the axon density. Treatment with aminoguanidine for 3 years had no effect on glycaemic control and did not restore conduction velocity or autonomic dysfunction in the diabetic animals, contrary to the studies in rats.¶Conclusions/interpretation. These results show that the primate is a good model to study diabetic neuropathy and suggest that the accumulation of advanced glycation end products are not an early mechanism of nerve damage in this disorder. [Diabetologia (2000) 43: 110–116]     

The Splanchnic Circulation and Postural Hypotension in Diabetic Autonomic Neuropathy

Postural hypotension results from sympathetic failure to cause superior peripheral vasoconstriction. The importance of the splanchnic circulation was studied by measuring mesenteric artery blood flow with duplex Doppler scanning. Nine normal and 9 Type 1 diabetic controls were compared to 8 Type 1 patients with autonomic neuropathy whose pressure fell 40–113 mmHg (range) on tilting. Measurements were made supine and after vertical tilt, fasting without insulin and after a 550 kcal meal. Superior mesenteric artery diameter decreased on tilting in normal controls but not in diabetic control or neuropathy groups (supine vs tilted: controls. 6.3 ± 0.9 to 5 ± 0.9 mm, p = 0.004, diabetic controls: 6.0 ± 0.6 to 6.0 ± 1.0 mm, and neuropathy group: 6.4 ± 0.9 to 5.6 ± 0.9 mm), but proportional blood flow changes were similar in all subjects (controls: 407 ± 154 to 255 ± 67 ml min^?1 (-31%, p = 0.03), diabetic controls: 379 ± 140 to 306 ± 149 ml min^?1 (-8%, p = 0.28), neuropathy group: 639 ± 371 to 435 ± 142 ml min^?1 (-23%, p = 0.10). Postprandially supine superior mesenteric artery flow increased in all subjects but this did not affect the degree of systolic blood pressure drop on tilting (fasting vs postprandial blood flow: controls: 407 ± 154 to 775 ± 400 ml min^?1 (p = 0.04), diabetic controls: 379 ± 140 to 691 ± 262 ml min^?1 (p = 0.01), neuropathy group: 639 ± 371 to 943 ± 468 ml min^?1 (p < 0.06)). The similarity of superior mesenteric artery responses to tilting in the three groups, and the lack of exacerbation of postural hypotension in the presence of postprandial hyperaemia indicates that control of splanchnic blood flow is less important in the aetiology of diabetic autonomic postural hypotension than previously thought.     

Vascular factors in diabetic neuropathy

Summary Despite considerable research we still do not have a comprehensive explanation for the pathogenesis of diabetic neuropathy. Although chronic hyperglycaemia is almost certainly involved, it is not known whether the primary pathology is metabolic, microvascular, or an interaction between the two. Hyperglycaemia-induced polyol pathway hyperactivity associated with nerve sorbitol accumulation and myo-inositol depletion may play a part in the genesis of diabetic neuropathy. The case for microvascular disease in diabetic neuropathy is now strong. Fibre loss in human sural nerve is multifocal, suggesting ischaemia. The degree of vessel disease has been related to the severity of neuropathy. People with chronic obstructive pulmonary disease develop the so called hypoxic neuropathy in which similar microvascular changes occur as in diabetic neuropathy. In rats with experimental diabetic neuropathy nerve blood flow is reduced and oxygen supplementation or vasodilator treatment improved the deterioration in conduction velocity and nerve blood flow. Similarly, in human diabetic neuropathy, there is impaired nerve blood flow, epineurial arterio-venous shunting and a reduction in sural nerve oxygen tension. At what stage during the development of nerve damage these changes occur is yet to be determined.Abbreviations RICF resistance to ischaemic conduction failure     

Persistent Postoperative Complaints After Whole Sural Nerve Biopsies in Diabetic and Non-diabetic Subjects

The postoperative effects of a whole sural nerve biopsy in diabetic (11) and non-diabetic (10 healthy controls, 10 patients with impaired glucose tolerance and 2 patients with polyneuropathy) subjects were investigated by a mailed questionnaire 20–44 months after the surgical procedure (10/11 vs 21/22 answers received). Pain in the biopsy area at follow-up was reported in 4/10 of the diabetic patients (p = 0.01) but in none of the non-diabetic subjects (0/21). An increased number (p = 0.01) of diabetic patients (5/10 vs 1/21) had cold intolerance in their foot or leg whereas 11/31 of all patients had dysaesthesia in the affected skin. Overall 6/31 patients described serious problems at the time of the questionnaire, and 4 of this 6 having diabetes. Loss of sensation was reported in almost all subjects irrespective of diabetes or not; however, a decrease in the area of loss of sensation was reported most often in diabetic patients (8/10 vs 8/21, p = 0.02). It is concluded that whole surval nerve biopsies give rise to persistent problems both in diabetic and non-diabetic subjects. The reason for a sural nerve biopsy has always to be carefully considered before being conducted. © 1997 by John Wiley & Sons, Ltd.     

Haemodialysis is associated with changes in cutaneous microcirculation in diabetes mellitus

Aims To examine the cutaneous microcirculation on the dorsum of the foot before, during and after haemodialysis in diabetic and non‐diabetic patients. Methods Fourteen age‐matched patients (seven diabetic, seven non‐diabetic) without active foot ulceration were studied. Cutaneous microcirculation was assessed using a micro‐lightguide spectrophotometer to measure venous oxygen saturation and relative blood flow determined at two tissue depths: 2 and 6 mm. Cumulative relative changes of each parameter during haemodialysis were calculated as area under the curve. Differences between and within the groups were calculated by Mann–Whitney U‐test and anova following post hoc testing, respectively. Results At baseline, relative blood flow at 6 mm tissue depth was significantly greater in diabetic patients (P = 0.048). Thirty minutes after the end of dialysis, relative blood flow at 2 and 6 mm tissue depth was significantly higher in non‐diabetic patients (P = 0.048 and P = 0.001). Mean cumulative relative changes in venous oxygen saturation and relative blood flow at 2 mm as well as 6 mm tissue depth were positive for non‐diabetic subjects and negative for diabetic patients. Conclusions Haemodialysis is associated with changes in cutaneous microcirculation, which differ between people with and without diabetes. In those without diabetes, we found an increase in blood flow during haemodialysis, whereas blood flow was reduced in diabetic patients. This may be the result of abnormal vasomotor regulation due to distal neuropathy.     

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.     

Autonomic neuropathy and transcutaneous oxymetry in diabetic lower extremities

Summary Transcutaneous oxygen tension is a useful method with which to assess the functional status of skin blood flow. The reduced values observed in diabetic patients have been interpreted as a consequence of peripheral vascular disease. However, diabetic patients show lower transcutaneous oxygen tension values than control subjects with equivalent degrees of peripheral vascular disease, suggesting that additional factors are involved. Since the autonomic nervous system influences peripheral circulation, we studied the relationship between autonomic neuropathy and foot transcutaneous oxymetry in non-insulin-dependent diabetic (NIDDM) patients without peripheral vascular disease. The following age-matched patients were selected and evaluated: control subjects, C, (n=20), NIDDM patients without autonomic neuropathy, D, (n=16) and with autonomic neuropathy, DN, (n=20). All diabetic patients showed lower transcutaneous oxygen tension values than control subjects, while no differences were observed between the diabetic patients with and without autonomic neuropathy. In addition the saturation index that increases in the presence of autonomic neuropathy does not correlate with foot TcPO₂. In conclusion autonomic neuropathy does not influence foot TcPO₂ and therefore it is unlikely that it contributes to development of foot lesions during induction of foot skin ischaemia.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - TcPO₂ transcutaneous oxymetry - A-V arterio-venous shunts - PVD peripheral vascular disease - HbA_1c glycated haemoglobin - SI saturation index     

Day and night variation in ambulatory blood pressure in type 1 diabetes mellitus with nephropathy and autonomic neuropathy

Abstract. The objective was to study ambulatory blood pressure and heart rate variability between day and night in patients with type 1 (insulin-dependent) diabetes mellitus with different degrees of diabetic nephropathy, and to evaluate the influence of autonomic neuropathy and type of antihypertensive treatment. Twenty type 1 diabetic patients with diabetic nephropathy and antihypertensive treatment were studied with 24-h ambulatory blood pressure monitoring using an oscillometric method. They were compared with eight insulin-treated diabetic patients with short duration of diabetes (1–5 years) and with 10 apparently healthy subjects. The degree of autonomic neuropathy was evaluated by measuring the RR-interval during deep breathing and uprising. The 24-h blood pressure was generally higher in patients with diabetic nephropathy compared to those other two groups. These patients also had a lower ratio between day and night in diastolic blood pressure compared to the control subjects (1.15 ± 0.12 vs. 1.25 ± 0.76, P < 0.05) and heart rate compared to the diabetic patients without nephropathy, as well as the control subjects (1.15 ± 0.08 vs. 1.26 ± 0.09 vs. 1.27 ± 0.08, P < 0.01, respectively). All patients with diabetic nephropathy had clinical signs of autonomic neuropathy as judged by RR-interval measurements during deep breathing and uprising.     

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.     

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.     

Effects of epalrestat,an aldose reductase inhibitor,on diabetic peripheral neuropathy in patients with type 2 diabetes,in relation to suppression of Nɛ-carboxymethyl lysine

ObjectiveWe investigated the efficacy of epalrestat, an aldose reductase inhibitor, for diabetic peripheral neuropathy in Japanese patients with type 2 diabetes.MethodsA total of 38 type 2 diabetic patients (22 men and 16 women; mean±S.E.M. age 63.3±1.0 years; duration of diabetes 9.6±0.8 years) with diabetic neuropathy were newly administered 150 mg/day epalrestat (EP group). Motor nerve conduction velocity (MCV), sensory nerve conduction velocity (SCV), and minimum F-wave latency were evaluated before administration of epalrestat and after 1 and 2 years. Serum N^?-carboxymethyl lysine (CML) as a parameter of advanced glycation end products (AGEs), lipid peroxide, and soluble vascular cell adhesion molecule (sVCAM)-1 as a parameter of angiopathy were measured before administration and after 1 year. We compared the results with those of 36 duration of diabetes-matched type 2 diabetic patients (mean±S.E.M. duration of diabetes 8.2±0.7 years) as control (C group).ResultsThe EP group showed significant suppression of deterioration of MCV (P<.01) and minimum F-wave latency (P<.01) in the tibial nerve and SCV (P<.05) in the sural nerve compared to those in the C group after 2 years. There was a significant difference in change in CML level between groups (?0.18±0.13 mU/ml in the EP group vs. +0.22±0.09 mU/ml in the C group, P<.05) after 1 year.ConclusionsEpalrestat suppressed the deterioration of diabetic peripheral neuropathy, especially in the lower extremity. Its effects might be mediated by improvement of the polyol pathway and suppression of production of AGEs.     

Biopsy of the posterior interosseous nerve: a low morbidity method for assessment of peripheral nerve disorders

Aims The sural nerve is the commonest peripheral nerve biopsied to help in the diagnosis of peripheral neuropathy of unknown cause. However, associated complications limit its use. The aim was, as an alternative, to asses biopsy of the terminal branch of the posterior interosseous nerve (PIN) in the forearm. Methods PIN pathology was morphometrically quantified in 10 male patients with Type 2 diabetes and compared with six PIN biopsy specimens taken post mortem from male cadavers with no history of neuropathy or trauma. Results The PIN biopsy procedure provides a long (approximately 3 cm) mono‐ or bifascicular nerve biopsy with generous epineurial tissue and adjacent vessels. Our results show a significantly lower myelinated fibre density in subjects with diabetes [5782 (3332–9060)/mm²] compared with autopsy control material [9256 (6593–12 935)/mm², P < 0.007]. No postoperative discomfort or complications were encountered. Conclusions A reduction in myelinated fibre density has previously been shown to be a clinically meaningful measure of neuropathy in diabetic patients. We demonstrate similar findings using the PIN biopsy. The PIN biopsy procedure fulfils the criteria for nerve biopsy and was well tolerated by the patients. It may be a possible alternative to sural nerve biopsy to allow for diagnosis of neuropathy.     

Prospective Study of Autonomic Nerve Function in Type 1 and Type 2 Diabetic Patients: 24 Hour Heart Rate Variation and Plasma Motilin Levels Disturbed in Parasympathetic Neuropathy

To clarify the impact of autonomic neuropathy in diabetic patients, we have conducted a prospective study of 58 Type 1 and 51 Type 2 diabetic patients (investigated at baseline, after 4, and after 7 years). In Type 1 diabetic patients, the sympathetic nerve function (orthostatic acceleration and brake indices) and in Type 2 patients, parasympathetic nerve function (R-R interval variation; E/I ratio) deteriorated during 7 years of prospective observation. Symptoms of autonomic neuropathy were associated with signs of autonomic neuropathy (low brake indices) in Type 1 but not in Type 2 diabetic patients. In the latest assessment 24 h ECG recording was performed and blood samples assayed for neuropeptide Y (NPY) and motilin were obtained. Type 1 diabetic patients with parasympathetic neuropathy (abnormal E/I ratio) showed significantly lower SD value (less variation in the R-R intervals; 29 [17] vs 50 [16], [mean {interquartile range}]; p = 0.001) and higher postprandial plasma motilin values (70 [20] pmol I^?1 vs 50 [15] pmol I^?1; p< 0.01) than patients with normal parasympathetic nerve function. In Type 2 diabetic patients, sympathetic neuropathy (low brake indices) was associated with an increased frequency of ventricular extra systolic beats during 24 h ECG recording (r_s = 0.65; p<0.01). Postprandial plasma NPY levels were not associated with disturbed autonomic nerve function.     

Effect of cilostazol on experimental diabetic neuropathy in the rat

Summary Two proposed mechanisms of diabetic neuropathy are microvascular ischaemia and a reduction in Na,K-ATPase activity. We evaluated the effect of cilostazol, a drug that is both a potent phosphodiesterase inhibitor that normalizes nerve Na,K-AT-Pase and a vasodilator, on nerve blood flow (NBF) to determine whether it would improve experimental diabetic neuropathy. We examined whether epineurally applied cilostazol acted as a vasodilator on the peripheral nerve of normal and diabetic rats, and whether feeding the rats a cilostazol-supplemented diet could improve diabetic neuropathy. Cilostazol increased nerve blood flow (NBF) in a dose-dependent fashion with an EC₅₀ of 10^–5.74 mol/l. Cilostazol also normalized NBF in experimental diabetic neuropathy with a 10^–4 mol/l local application on the sciatic nerve. In diabetic neuropathy, a cilostazol-supplemented diet improved both NBF and nerve conduction in a dose- and time-dependent fashion. Potential mechanisms of action of cilostazol on the nerve include its effect on NBF, Na, K-ATPase, and restoration of the thromboxane:prostacyclin ratio. Cilostazol may have potential in the treatment of diabetic neuropathy.Abbreviations EDN Experimental diabetic neuropathy - NBF nerve blood flow - STZ streptozotocin - NRC control rats receiving normal diet - NRH control rats receiving a high (0.1%) cilostazol diet - CSH STZ rats receiving high (0.1%) cilostazol diet - CSL STZ rats receiving low (0.03%) cilostazol diet - CV conduction velocity     

Autonomic and Peripheral Nerve Function in Early Diabetic Neuropathy

ABSTRACT. Sundkvist G, Lilja B, Rosén I, Agardh C-D (Departments of Internal Medicine and Clinical Physiology, Malmö General Hospital, and Departments of Clinical Neurophysiology and Internal Medicine, University Hospital, University of Lund, Lund, Sweden). Autonomic and peripheral nerve function in early diabetic neuropathy. Possible influence of a novel aldose reductase inhibitor on autonomic function. Acta Med Scand 1987; 221:445–53. Autonomic and peripheral nerve functions as well as the possible short-term effect of a novel aldose reductase inhibitor (ARI) on neuropathy were evaluated in 30 male type I diabetics (age 25–44 years, mean 34; duration of diabetes 10–20 years, mean 34) with neurographic signs of peripheral neuropathy (PN). Autonomic neuropathy (AN) was established by the heart rate reactions to deep breathing (E/I ratio = vagal function) and to tilt (acceleration index = sympathetic and vagal functions; the brake index = vagal function). Twenty-nine patients, 13 with AN, completed the study. Among neurographic variables, only sural nerve function tests correlated with autonomic functions. Patients with AN showed significantly lower mean sensory action potential amplitudes (SAPA) sural, indicating axonal losses, than patients without AN (3.58±0.79 μV vs. 7.34±1.12 μV; p<0.01). PN as measured by neurography did not improve during ARI treatment. On the other hand, vagal function (brake indices) improved (p<0.05) during ARI in AN patients.     

Subclinical nerve dysfunction in children and adolescents with IDDM

Summary The purpose of this study was to investigate whether young insulin-dependent diabetic patients still develop peripheral nerve dysfunction when using modern multiple insulin injection therapy and to elucidate if this correlated with various disease parameters. Seventy-five patients, 7 to 20 years old with a duration of diabetes of more than 3 years, and 128 age-matched healthy control subjects underwent bilateral studies of median, peroneal, and sural nerves. Presence of diabetes lowered motor conduction velocity (p<0.0001), sensory conduction velocity (p<0.0001) and sensory nerve action potential (p<0.05) in all examined nerves. The mean change in conduction velocity induced by diabetes was –4.8 m/s in the peroneal nerve, –3.3 m/s in the median motor nerve, –2.6 m/s in the sural nerve and –2.4 m/s in the median sensory nerve. Fifty-seven percent of the patients had abnormal conduction (values outside 95% predictive interval) which was seen most often in the motor nerves, especially in the peroneal nerve (41%) followed by the median nerve (24%). In multiple regression analysis, long-term poor metabolic control and increased body length correlated with nerve dysfunction identified in most examined parameters. Three patients had signs or symptoms suggestive of neuropathy. It is concluded that despite modern multiple insulin injection therapy, with reasonably good metabolic control, nerve dysfunction is still common in children and adolescents with insulin-dependent diabetes mellitus. Risk factors are increased height and long-term poor metabolic control.Abbreviations IDDM Insulin-dependent diabetes mellitus - MIT multiple insulin injection therapy - MCV motor nerve conduction velocity - CMAP compound muscle action potential - DML distal motor latency - SCV sensory nerve conduction velocity - SNAP sensory nerve action potential