Update on diabetic neuropathy

PURPOSE OF REVIEW: This review will focus on recent advances in the field of diabetic neuropathy, with an emphasis on distal symmetric sensory and sensorimotor polyneuropathy. Some new information in the areas of diabetic amyotrophy and diabetic autonomic neuropathy will also be reviewed. RECENT FINDINGS: The pathogenesis of diabetic neuropathy is multifactorial. There is increasing evidence to link abnormalities in the polyol pathway to the pathogenesis of diabetic neuropathy. In addition, there appear to be abnormalities of nerve regeneration and of sodium and calcium channels. Aldose reductase inhibitors have shown promise in animal models for reversing neuropathy if started early and used for a sufficient time, but those used to date in human trials are probably not of sufficient potency. Neurotrophic factors and vascular endothelial growth factor both also show promise. Specific recommendations and pathways for diabetic foot care have been devised. Lamotrigine and bupropion represent new treatments for neuropathic pain. The role of impaired glucose tolerance is being explored as it relates to polyneuropathy. SUMMARY: An increasing understanding of the pathogenetic mechanisms holds out promise for the effective treatment of diabetic neuropathy. The early detection of abnormal glucose metabolism is particularly important, as treatments will probably be most effective if administered early in the course of the neuropathy, when abnormalities of peripheral nerves are more likely to be reversible.     

Is early diabetic neuropathy a disorder of the dorsal root ganglion? A hypothesis and critique of some current ideas on the etiology of diabetic neuropathy

Investigations into the etiology of diabetic polyneuropathy have largely concentrated on the mixed peripheral nerve trunk. Although a number of workers have suggested that reductions in mixed nerve blood flow account for early diabetic polyneuropathy, experimental results remain controversial and are not fully sustained by human studies. Later disease is unquestionably associated with microangiopathy. Patients with diabetic neuropathy may have exclusive and severe sensory and autonomic involvement without obvious motor disease. The prominent sensory involvement in early diabetic polyneuropathy may suggest that the disease particularly targets dorsal root ganglia. Dorsal root ganglia (DRG) have features that might suggest they would be vulnerable to changes known to occur in diabetes, i.e. microangiopathy, excessive polyol flux and protein glycosylation. Autonomic ganglia may also be targeted early in the disease. The interest in using growth factors to treat diabetic neuropathy is at least partly based on the hypothesis that these agents might provide important trophic support for DRG neurons.     

Blink reflex alterations in diabetic patients with or without polyneuropathy

The main aim of this study is to evaluate the role of blink reflex for early diagnosis of cranial neuropathy in diabetic patients with or without polyneuropathy. Ninety-five diabetic patients were included in the present study for the evaluation of blink reflex. The diabetic patients were divided into two groups according to having diabetic neuropathy or not. Both R1, R2i and R2c latencies in all diabetic patients with or without polyneuropathy were prolonged relative to controls and the differences were statistically significant (p < .001). R1 latencies in diabetic patients with polyneuropathy were prolonged relative to diabetic patients without polyneuropathy and the differences were statistically significant (p < .001). These findings presumably reflect that facial nerve is severly involved in diabetic polyneuropathy. Finally blink reflex is of value in detection of clinically silent intraaxial brainstem functional abnormalities or extraaxial lesions in diabetic patients before peripheral neuropathy.     

Polyglucosan bodies in the sural nerve of a diabetic patient with polyneruopathy

Summary In the sural nerve of a 62-year-old woman with impaired glucose tolerance test and polyneuropathy, many intra-axonal polyglucosan bodies were observed. Polyglucosan bodies have been described in spontaneously or alloxan-diabetic rats, but are not usually observed in human diabetic neuropathy. Since intra-axonal polyglucosan bodies can occur in the sural nerve in various diseases and in aging, they are considered as non-specific changes. Their presence is probably related to a primary axonal neuropathy.Supported in part by CNR (Center for Cerebral Neurophysiclogy, Genova) and by CNR contract no. 83.02062.04     

Femoral nerve involvement in diabetics

Background and purpose:  In this study, the conduction of the femoral nerve has been evaluated in diabetic patients without clinical signs of femoral nerve involvement and in a group of healthy subjects.
Methods:  Forty-eight patients have been included in the study. Patients have been examined in terms of neuropathy and their neuropathy scores have been calculated. In addition to the nerve conduction studies have been performed. The findings of the diabetic patients have been compared with those of the 26 healthy volunteers.
Results:  There has been a statistically significant difference between diabetics and the healthy volunteers in the control group in terms of both femoral nerve motor latency and amplitude. The femoral latencies of patients have significantly been related to the total neuropathy score. A significant difference between diabetic patients without polyneuropathy and the controls was observed with respect to their femoral latencies.
Conclusion:  In our study, femoral nerve conduction abnormalities have been determined in diabetics who clinically did not have femoral nerve involvement. It has been observed that these abnormalities become more evident as the polyneuropathy of the patients becomes more serious. Our study has shown that femoral nerve conductions may increase the sensitivity of the diagnosis of polyneuropathy.     

Paranodal structure in diabetic sensory polyneuropathy

Observations have been made on the structure of the paranodal region at nodes of Ranvier in the sural nerve of patients with diabetic sensory polyneuropathy. The structure of the paranodes was examined with particular attention to the definition and assessment of axoglial dysjunction, which has been claimed to be a characteristic feature of both human and experimental diabetic neuropathy and which has been related to paranodal swelling. In the present series of cases it was not possible to confirm that axoglial dysjunction is a distinctive feature of diabetic polyneuropathy in fibres not undergoing active demyelination or wallerian-type degeneration, neither was excessive paranodal enlargement found. Received: 11 March 1996 / Revised, accepted: 10 June 1996     

The role of axonal ion conductances in diabetic neuropathy: A review

Diabetic neuropathy is a common complication in diabetes mellitus. Diabetic neuropathy is accompanied by alterations in axonal excitability, which can lead to either “positive” (paresthesia, dysesthesia, pain) and/or “negative” (hypesthesia, anesthesia) symptoms. The mechanisms underlying these alterations in axonal excitability are not well understood. Clinical tests reveal reduced nerve conduction velocity and axonal loss, but fail to explain nerve excitability. Many different factors have been suggested in relation to the pathophysiology of diabetic neuropathy. There are probably as many factors as there are different clinical pictures in diabetic neuropathy. Nevertheless, it seems that hyperglycemic hypoxia is mainly responsible for the electrophysiological changes seen in damaged diabetic nerves. This article summarizes experimental data indicating that a dysfunction of ion conductances, especially voltage-gated ion channels, could contribute to abnormalities in the generation and/or conduction of action potentials in diabetic neuropathy. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1246–1255, 1998.     

Diabetic neuropathy: An update

Diabetic neuropathy is the most common neuropathy in industrialized countries, with a remarkable range of clinical manifestations. The usual pattern is a distal symmetrical sensory polyneuropathy, associated with autonomic disturbances. Less often, diabetes is responsible for a focal or multifocal neuropathy affecting cranial nerves, especially oculomotor nerves, and roots and nerves innervating proximal muscles of the lower limbs. Metabolic abnormalities due to hyperglycaemia, lack of insulin and their consequences and ischaemic phenomena secondary to diabetic microangiopathy account for nerve lesions.     

Hypoxic neuropathy versus diabetic neuropathy An electrophysiological study in rats

In the experimental rat model of diabetes a slowing of nerve conduction velocity and a resistance to ischemic conduction failure have been found as an indication of polyneuropathy. The same electrophysiological abnormalities have been demonstrated in a model in which healthy rats are kept under hypoxic conditions (10% O₂) for a 10-week period. Two factors are held responsible for the development of diabetic polyneuropathy: metabolic deterioration and hypoxia. However, until now the relative roles of metabolic deterioration and hypoxia in the development of polyneuropathy have not been settled. To test both explanations further with more sophisticated electrophysiological techniques, the H-reflex (motor and sensory NVC) and the stimulated SF-EMG (measures terminal nerve branch and neuromuscular transmission) were measured in 3 groups of 10 rats, a healthy control group, a diabetic group, and a hypoxic group, every 5 weeks, for 6 months. In the control rats an age-related increase in motor and sensory conduction velocity was found, whereas in the diabetic rats as well as in the hypoxic rats a marked decrease in sensory and a slight decrease in motor nerve conduction velocity was observed. The jitter measured in the stimulated SF-EMG was significantly increased in both the diabetic and the hypoxic group. The results of the present study support the possible role of hypoxia, in addition to metabolic factors, in the development of experimental diabetic neuropathy.     

Effect of NGF and neurotrophin-3 treatment on experimental diabetic autonomic neuropathy

Peripheral neuropathy is a significant complication of diabetes resulting in increased patient morbidity and mortality. Deficiencies of neurotrophic substances (e.g. NGE NT-3, and IGF-I) have been proposed as pathogenetic mechanisms in the development of distal symmetrical sensory diabetic polyneuropathy, and salutary effects of exogenous NGF administration have been reported in animal models. In comparison, relatively little is known concerning the effect of NGF on experimental diabetic sympathetic autonomic neuropathy. We have developed an experimental animal model of diabetic autonomic neuropathy characterized by the regular occurrence of pathologically distinctive dystrophic axons in prevertebral sympathetic ganglia and ileal mesenteric nerves of rats with chronic streptozotocin (STZ)-induced diabetes. Treatment of STZ-diabetic rats for 2-3 months with pharmacologic doses of NGF or NT-3, neurotrophic substances with known effects on the adult sympathetic nervous system, did not normalize established neuroaxonal dystrophy (NAD) in diabetic rats in the prevertebral superior mesenteric ganglia (SMG) and ileal mesenteric nerves as had pancreatic islet transplantation and IGF-I in earlier experiments. NGF treatment of control animals actually increased the frequency of NAD in the SMG. New data suggests that, in adult sympathetic ganglia. NGF may contribute to the pathogenesis of NAD rather than its amelioration, perhaps as the result of inducing intraganglionic axonal sprouts in which dystrophic changes are superimposed. NT-3 administration did not alter the frequency of NAD in diabetic animals, although it resulted in a significant decrease in NAD in control SMG. Although deficiencies of neurotrophic substances may represent the underlying pathogenesis of a variety of experimental neuropathies, delivery of excessive levels of selected substances may produce untoward effects.     

Interdigital nerve conduction study of the foot for an early detection of diabetic sensory polyneuropathy.

OBJECTIVE: To report on the value of interdigital nerve (IDN) conduction study (NCS) of the foot for the recognition of diabetic sensory polyneuropathy with normal routine NCS and the nature of electrophysiological abnormality in early diabetic sensory polyneuropathy. METHODS: The sensory nerve conductions in the two digital and 4 IDNs of the foot were obtained orthodromically using the near-nerve needle and signal averaging technique. RESULTS: In 21 patients with diabetic sensory polyneuropathy with normal routine NCS, a definite neuropathy pattern (abnormalities in more than 3 of 6 tested nerves) was observed in 12 patients (57.1%). The most common abnormalities that were found were a low amplitude in the sensory compound nerve action potential and an absent potential, indicating that early diabetic sensory polyneuropathy is due to axonal degeneration. CONCLUSIONS: Interdigital NCS of the foot using near-nerve needle technique can identify neuropathy in diabetic sensory polyneuropathy with normal routine NCS. This technique offers a useful means of detecting nerve conduction abnormalities in the early stage of diabetic polyneuropathy.     

Recent advances in the pathogenesis of diabetic neuropathy

Recent advances in the understanding of the pathogenesis of diabetic neuropathy have been made in six areas. There is support for the notion that a reduction in nerve free myoinositol may be responsible in part for the nerve conduction slowing in diabetic neuropathy. There is further evidence of microvascular abnormalities, including morphometric evidence of multifocal fiber loss and of capillary changes in biopsied sural nerve. There is evidence of endoneurial hypoxia, including the findings of reduced nerve blood flow and endoneurial oxygen tensions in chronic experimental diabetic neuropathy (EDN). The major mechanisms of resistance to ischemic conduction failure (RICF) is the marked increase in nerve energy substrates. Recent studies provide certain insights into clinical characteristics of human diabetic neuropathy (HDN), including the asymmetric pattern of HDN, the paradox between liability to pressure palsies and RICF, and insulin-related acute painful neuropathy. The suggested pathogenetic scheme incorporates the notion that once hypoxia is established, it may start a vicious cycle of further capillary damage and escalating hypoxia.     

Fiber loss is primary and multifocal in sural nerves in diabetic polyneuropathy

Pathological, morphometric, and teased fiber studies of sural nerve from 36 diabetic patients with (n = 32) and without (n = 4) neuropathy and from 47 healthy subjects provide evidence that in diabetic polyneuropathy: (1) fiber loss is primary; (2) demyelination and remyelination with or without onion bulb formation are secondary; (3) remaining fibers, on average, have the same ratio of small to large fibers as in healthy individuals, but with a greatly increased variability; and (4) the spatial distribution of fiber loss is both diffuse and multifocal. Criteria developed during the study of experimental models of ischemic neuropathy were employed to assess whether ischemic nerve damage had occurred in diabetic polyneuropathy. We conclude that there is increasing evidence that microvascular pathological abnormality and ischemia may be involved in the pathogenesis of human diabetic polyneuropathy. Cases with selective loss of small or large afferent fibers are probably extremes of a normal distribution and not different disorders.     

High resolution sonography in the evaluation of the peripheral nervous system in polyneuropathy – a review of the literature

Clinical, laboratory and electrodiagnostic studies are the mainstay in the diagnosis of polyneuropathy. An accurate etiological diagnosis is of paramount importance to provide the appropriate treatment, prognosis and genetic counselling. High resolution sonography of the peripheral nervous system allows nerves to be readily visualized and to assess their morphology. Ultrasonography has brought pathophysiological insights and substantially added to diagnostic accuracy and treatment decisions amongst mononeuropathies. In this study the literature on its clinical application in polyneuropathy is reviewed. Several polyneuropathies have been studied by means of ultrasound: Charcot–Marie–Tooth, hereditary neuropathy with liability to pressure palsies, chronic inflammatory demyelinating polyneuropathy, Guillain‐Barré syndrome, multifocal motor neuropathy, paraneoplastic polyneuropathy, leprosy and diabetic neuropathy. The most prominent reported pathological changes were nerve enlargement, increased hypo‐echogenicity and increased intraneural vascularization. Sonography revealed intriguingly different patterns of nerve enlargement between inflammatory neuropathies and axonal and inherited polyneuropathies. However, many studies concerned case reports or case series and showed methodological shortcomings. Further prospective studies with standardized protocols for nerve sonography and clinical and electrodiagnostic testing are needed to determine the role of nerve sonography in inherited and acquired polyneuropathies.     

THE EXTRACELLULAR MATRIX OF PERIPHERAL NERVE IN DIABETIC POLYNEUROPATHY

The pattern of collagenisation in peripheral nerve in diabetic polyneuropathy was examined in nerve biopsy specimens from patients with diabetic polyneuropathy in comparison with organ donor control nerves and disease controls (other neuropathies). There was increased endoneurial collagenisation both in the diabetic polyneuropathy cases and the disease controls, this predominantly involving types I and III. Type II collagen was not detected in organ donor control nerves or in the diabetic and the disease control nerves. There was a relative increase in type VI collagen in the endoneurium in the diabetic nerves immediately surrounding groups of Schwann cells. This was not a feature in the other neuropathies. The quantity of types IV, V and VI collagen was increased around the endoneurial microvessels in the diabetic patients and, to a lesser extent, in those with hereditary motor and sensory neuropathy (HMSN). Increased deposition of types IV and V collagen was observed in the perineurium in the diabetic nerves, the latter being most evident in the innermost lamellae where the amount of laminin was possibly also increased. The diameter of the general endoneurial collagen fibrils was greater in the diabetic nerves, although this was not more than in a disease control (HMSN). The collagen fibrils that were present within the basal laminal tubes that had surrounded degenerated myelinated fibres in the diabetic nerves, and those within the onion bulbs of the HMSN cases, were of the normal endoneurial calibre. The expression of laminin by Bungner bands in diabetic neuropathy did not differ from that in disease control nerves, nor were any differences detected for fibronectin. Whether the changes observed are important for the impaired regenerative capacity in diabetic neuropathy requires further investigation.     

Peripheral neuropathy in essential mixed cryoglobulinaemia.

The prevalence of various forms of peripheral neuropathy has not been previously assessed in large series of patients with essential mixed cryoglobulinaemia (EMC). Clinical and electrophysiological signs of peripheral neuropathy were observed in 21 of 37 EMC patients, consisting of polyneuropathy in 19, mononeuropathy or multiple mononeuropathy in eight, and both in six. The various forms of peripheral neuropathy occurred differently in the subgroups of EMC. Isolated polyneuropathy was more common with type II (eight of 10) than type III EMC (two of eight). Multifocal neuropathy, in association with polyneuropathy, was the most common form in type III EMC (five of eight). Patients with peripheral neuropathy and type II EMC were significantly older than type II EMC patients without neuropathy, regarding present age and age of onset of EMC. Patients with peripheral neuropathy and type III EMC tended to have higher values of ESR and IgM than type III EMC patients without neuropathy. Electrophysiological findings and sural nerve biopsy specimens (nine cases) showed prominent axonal changes. Vascular changes included vasculitis and alterations of the endoneurial microvessels in type II and type III EMC. Our findings suggest that distinct pathogenic factors are implicated in the subgroups of cryoglobulinaemic neuropathy, possibly inducing different types of vascular changes underlying polyneuropathy or, respectively, mononeuropathy and multiple mononeuropathy.     

Peripheral neuropathy in patients with diabetic foot ulcers: clinical and nerve conduction study

OBJECTIVES: Diabetic foot lesions develop predominantly in male patients and sensory neuropathy is the most frequent type of neuropathy associated with these lesions. The aim of this study was to analyze the clinical and electrophysiological features in a cohort of patients with diabetic foot. RESEARCH DESIGN AND METHODS: The recordings of 318 consecutive diabetic patients (127 women and 191 men) with an ongoing or healed foot ulcer who had been referred for electrophysiological consultation were evaluated retrospectively. RESULTS: 60.1% of our cohort were male. Loss of deep sensation and deep tendon reflex abnormalities were the most common neurological findings. Negative sensory symptoms (63.7% vs 40.8%, p<0.01) and neuropathic pain (38.5% vs 18.3%, p<0.01) were more frequent in females, whereas atrophy was more frequent in male patients (22.8% vs 46%, p<0.01). Motor nerve conduction abnormalities and ulnar nerve involvement was more frequent and severe in males. Abnormal electrophysiological findings were mild in 70 patients (female 42, 60%). In this group, hemiplegia, peripheral arterial disease, multiple bone fractures, end stage renal failure, recent pulmonary tuberculosis and dementia accompanied mild polyneuropathy. Thirty patients had shown prominent decrease in nerve conduction velocity which indicated severe demyelination. Among these 30 patients, 6 male subjects had clinical features similar to that of chronic inflammatory demyelinating polyneuropathy. CONCLUSIONS: Our results indicate that male gender, motor neuropathy and mononeuropathies, especially ulnar neuropathy is associated with the development of DF among our patients with DF. Patients with diabetes mellitus have a predisposition to develop chronic inflammatory demyelinating polyneuropathy and this may also facilitate formation of diabetic foot. History of hemiplegia, dementia and trauma are permissive risk factors for diabetic foot in the presence of mild polyneuropathy.     

Diabetic neuropathy

Peripheral nerve disorders are important late complications of diabetes mellitus. Polyneuropathy, which may involve varying proportions of sensory, motor, and autonomic fibers, is considered the consequence of metabolic derangements that result from chronic hyperglycemia. Symmetrical proximal motor neuropathy ("diabetic amyotrophy") also may have a metabolic basis. Mononeuropathies in diabetes may have an ischemic or compressive cause. Advances have been made in understanding the biochemical basis for diabetic polyneuropathy. The treatment of symptomatic diabetic neuropathy should be directed toward long-term normalization of blood glucose until more specific therapies become available.     

The extracellular matrix of peripheral nerve in diabetic polyneuropathy

The pattern of collagenisation in peripheral nerve in diabetic polyneuropathy was examined in nerve biopsy specimens from patients with diabetic polyneuropathy in comparison with organ donor control nerves and disease controls (other neuropathies). There was increased endoneurial collagenisation both in the diabetic polyneuropathy cases and the disease controls, this predominantly involving types I and III. Type II collagen was not detected in organ donor control nerves or in the diabetic and the disease control nerves. There was a relative increase in type VI collagen in the endoneurium in the diabetic nerves immediately surrounding groups of Schwann cells. This was not a feature in the other neuropathies. The quantity of types IV, V and VI collagen was increased around the endoneurial microvessels in the diabetic patients and, to a lesser extent, in those with hereditary motor and sensory neuropathy (HMSN). Increased deposition of types IV and V collagen was observed in the perineurium in the diabetic nerves, the latter being most evident in the innermost lamellae where the amount of laminin was possibly also increased. The diameter of the general endoneurial collagen fibrils was greater in the diabetic nerves, although this was not more than in a disease control (HMSN). The collagen fibrils that were present within the basal laminal tubes that had surrounded degenerated myelinated fibres in the diabetic nerves, and those within the onion bulbs of the HMSN cases, were of the normal endoneurial calibre. The expression of laminin by Büngner bands in diabetic neuropathy did not differ from that in disease control nerves, nor were any differences detected for fibronectin. Whether the changes observed are important for the impaired regenerative capacity in diabetic neuropathy requires further investigation. Received: 11 August 1997 / Revised, accepted 16 August 1999