Role For Oxidativenitrosative Stress

Enhanced oxidative stress, resulting from imbalance between production and neutralization of ROS is a well-recognized mechanism in the pathogenesis of PDN. Recently, considerable progress has been made in the detection of diabetes-associated oxidative injury in PNS. New studies (20,21,36,41,45,81) have confirmed previously established lipid peroxidation product accumulation, GSH depletion and increase in GSSG GSH ratio, and downregulation of superoxide dismutase (SOD) activity in the diabetic...

Role For Pkc Activation

PKC includes a superfamily of isoenzymes, many of which are activated by 1,2-diacylglycerol in the presence of phosphatidylserine. PKC isoforms phosphorylate a wide variety of intracellular target proteins and have multiple functions in signal trans-duction-mediated cellular regulation. The role for PKC in the pathogenesis of PDN has been reviewed in detail (80). PKC is activated in vasa nervorum of diabetic rats (81), and vessel-rich epineurial vessels of diabetic mice (82). PKC has been...

Therapies For Nerve Regeneration

Neurotrophic factors are proteins that promote survival of neurons regulating gene expression through second messenger systems. These proteins may induce morphological changes, nerve differentiation, nerve cell proliferation, and induce neurotransmitter expression and release. Subsequently, reduction in levels of neurotrophic factors (97) can lead to neuronal loss, possibly through activation of apoptosis (98). Many proteins have properties and characteristics of neurotrophic factors, including...

Clinical Trials With Aris

Alrestatin was the first ARI to be tried in human diabetic neuropathy. In the first, uncontrolled study conducted in 1981, 10 patients with symptomatic neuropathy were treated with intravenous infusions of alrestatin for 5 days (5). Although, symptomatic improvement was noticed in seven patients, objective measurements failed to improve. Therefore, as the trial was not controlled, a placebo effect accounting for the symptomatic improvement cannot be excluded. No adverse effects of alrestatin...

Therapies Targeting Autoimmunity

Traditional therapies for autoimmune neuropathies have proven beneficial for certain types of diabetic neuropathy (94). Plasmaphoresis and steroidal anti-inflammatories should be considered if the diagnosis is proximal diabetic neuropathy (diabetic amyo-trophy) or demyelinating neuropathy. Failure of these treatments or evidence of auto-immunity in typical diabetic polyneuropathy might warrant anti-immune approaches. Immune intervention with human intravenous immunoglobulin (IVIg) has become...

Spinal Neurochemistry In Diabetes

The structural and electrophysiological properties of the spinal cord during diabetes described earlier present a picture that resembles the paradox often noted in studies of the peripheral nerve, namely structural and electrophysiological indices of progressive degeneration and functional loss that are accompanied by increased activity in some sensory fibers and associated with hyperalgesia, allodynia, or spontaneous pain. There has been speculation that the spontaneous or enhanced activity of...

Treatment Of Focal Diabetic Neuropathies

Cranial nerve palsies improve spontaneously and do not require specific treatment. PDN is often very painful and should be treated, for example, with paracetamol (acetaminophen) and codeine. As some patients with disabling painful proximal neuropathy responded only to corticosteroids, this treatment should be considered in severe forms (32). This will require adjustment of diabetic control with insulin in most cases. Others have suggested the use of immunosuppressive or immunomodulators, like...

QoL And Neuropathic Pain

It is well-recognized that painful symptomatology, and also neuropathic deficits, might have an adverse effect on the QoL in diabetic neuropathy (21,22). It is increasingly recognized that QoL, rather than being a mere rating of health status, is actually a uniquely personal experience, representing the way that individuals perceive and react to their health status (23). This increasing recognition emphasizes the need to address the patient's perspective, rather than the researchers' views when...

End Points For Clinical Trials In Diabetic Neuropathy

Among the challenges for studies of diabetic neuropathy is the selection of the measures that can be used to determine the efficacy of the agents. Common end points include 1. Subjective measures of symptoms (e.g., nerve symptom scores). 2. Questionnaires that allow for quantification of any changes in the symptoms of diabetic neuropathy, or the quality of life of the patient (e.g., neuropathy symptom scores, total neuropathy scores). 3. Objective neurological examinations focussing on distal...

Oxidative And Nitrosative Induced Cell Death In Diabetic Neuropathy

Hyperglycemia promotes production of superoxides (O , increases flux through the Mt electron transport chain, and might be responsible for most of the key features of oxidative stress (20,23,54,55). In cell culture models of hyperglycemia, inhibition of formation prevents glucose-induced formation of advanced glycation end products (AGEs) and activation of protein kinase-C (56). O2 can also react with nitric oxide (NO) to form peroxynitrite (ONOO), which can damage intracellular lipids and...

Macrovascular Disease And Diabetic Neuropathy

Conventional risk factors for macrovascular disease, such as hypertension, raised triglyceride levels, body mass index, and smoking have been shown to be independent predictors of the development of diabetic neuropathy (57). The link between these classical cardiovascular risk factors and diabetic microvascular complications, including neuropathy is not clear, but the development of atherosclerosis of the lower extremities might be one possible explanation. Several of the risk factors...

Clinical Symptoms

Symptomatic diabetic neuropathy might affect 30-40 of diabetic patients with neuropathy. The most commonly reported symptom is pain in the distal extremities, in the legs more than in the arms with nocturnal exacerbation. Patients report deep aching pain, a burning feeling, sharp shock-like pain, or a more constant squeezing sensation (pressure myalgia). These symptoms are called positive sensory symptoms because of apparent hyperactivity of nerves and perceived as a presence of something that...

Blood Flow Of Nerve Trunks And Ganglia

The characteristics of the blood flow in nerve trunks and ganglia are unique and are distinguished from those of the central nervous system. Nerve trunks are supplied upstream by arterial branches of major limb vessels that share their supply with other limb tissues. At some sites, the overlapping vascular supply from several parent vessels renders zones of susceptibility to ischemia, or watershed zones. In the rat, and probably human sciatic nerve, a watershed zone can be found in the proximal...

SUMMARY

Diabetes mellitus is a condition that might result in a variety of derangements of gastrointestinal (GI) structure and function. Disturbances may manifest as symptoms and metabolic changes that in turn, might impich in the management of the patient with diabetes. The present chapter describes the pathophysiology, clinical findings, and management options dealing with the main clinical syndromes associated with disturbances of GI physiology in diabetics. It deals with esophageal dysfunction,...

Lower Extremity Arterial Disease And Diabetes

The concomitant occurrence of atherosclerotic peripheral vascular disease and peripheral neuropathy in patients with diabetes is the main factor in the development of diabetic foot pathology. Although neuropathy has proven the main risk factor for foot ulceration, peripheral arterial disease of the lower extremities is considered the major risk factor for lower-extremity amputation and it is also accompanied by a high likelihood for cardiovascular and cerebrovascular diseases (45). The rate of...

Inhibitors Of Glycation

It is apparent that advanced glycosylation end products (AGEs) contribute to nerve damage either by direct action on neurons and myelin or by enhancing oxidative stress under hyperglycemic conditions. Thus, there is a great deal of interest in agents that either prevent the formation of AGEs or agents that reverse the nonenzymatic glycation of proteins. Animal studies using aminoguanidine, an inhibitor of the formation of AGEs, showed improvement in nerve conduction velocity in rats with...

Apoptosis In The Sc

Despite the abundance of SC in the peripheral nerve, less is known about SC than DRG apoptosis in the diabetic PNS. Several lines of evidence support morphological changes of apoptosis in SC in vitro, in models of diabetic neuropathy, and in human diabetic neuropathy (22,110). SC obtained from the dorsal root of diabetic animals exhibit chromatin clumping and disruption of the myelin surrounding atrophic axons (Fig. 3) (110). Schwann-like satellite cells from corresponding diabetic DRG show...

Role For Ar

The sorbitol pathway of glucose metabolism consists of two reactions. First, glucose is reduced to its sugar alcohol sorbitol by NADPH-dependent AR. Then, sorbitol is oxidized to fructose by NAD-dependent SDH. Negative consequences of the sorbitol pathway hyperactivity under diabetic or hyperglycemic conditions include intracellular sorbitol accumulation and resulting osmotic stress, and generation of fructose, which is 10-times more potent glycation agent than glucose. One group reported that...

Diabetic Neuropathy In Western Medicine

John Rollo, a surgeon of the British Royal Artillery, was systematically studying diabetes. He was probably the first person to use the adjective mellitus (from the Latin and Greek roots for honey) to distinguish the condition from the similar one but without glycosuria (in Latin, insipidus means tasteless). He was the first one to recommend a diet low in carbohydrates as a treatment for diabetes. Rollo summarized his therapeutic experience with diabetes in a book published in 1798 (11). His...

Epidemiological Principles Relevant To The Study Of Diabetic Neuropathy

In order to understand published research on the epidemiology of diabetic neuropathy, certain principles of epidemiological study design must be taken into consideration. These principles guided these authors in the selection of relevant citations and data presentation. Cross-sectional or case-control studies conducted in a population-based sample (such as a defined community or health plan enrollment) were considered for this chapter based on review of Medline citations using the keywords...

Clinical Trial Design For Painful Neuropathy Trials

A number of considerations must be taken into account in the design of clinical trials to assess potential therapies for chronic painful sensorimotor neuropathy 1. Is this chronic neuropathy As noted earlier, there are two main types of painful symmetrical diabetic neuropathy acute painful neuropathy, which is relatively rare and typically presents after a period of poor glycemic control with severe symptoms and few signs. The natural history of this condition is one of improvement of symptoms...

Fbo

IGF-I, see Insulin-like growth factor-I IGT, see Impaired glucose tolerance Impaired glucose tolerance (IGT), diabetic neuropathy risk factor, 26, 231, 232 Incontinence, see Bladder dysfunction Fecal incontinence Inflammatory demyelinative polyneuropathy, diabetes association and clinical features, 375 Insulin-like growth factor-I (IGF-I) neuroprotection and signaling, 122, 136, 236, 237 therapeutic prospects, 329 Intravenous immunoglobulin (IVIg), clinical trials in diabetic neuropathy, 329...

Role For Downstream Effectors Of Ros Injury And Other Newly Discovered Mechanisms

One of the important effectors of oxidative-nitrosative injury and associated DNA single-strand breakage is activation of the nuclear enzyme PARP (113). Once activated, PARP cleaves nicotinamide adenine dinucleotide (NAD+) with formation of nicoti-namide and ADP-ribose residues, which are attached to nuclear proteins and to PARP itself, with formation of poly(ADP-ribosyl)ated protein polymers. The process leads to 1. NAD+ depletion and energy failure (26,27,113,114) 2. Changes of...

The Ancient Period

The first ever record of diabetes appears to be the papyrus named after the Egyptologist Ebers, who found it in an ancient grave in Thebes. It is written in hieroglyphs. The exact time of its writing is unknown, but most estimates date it around 1550 bc. It contains descriptions of a number of diseases including a polyuric state resembling diabetes, which was to be treated with a decoction of bones, wheat, grain, grit, green lead, and earth (1). The term diabetes was first used by Aretaeus of...

Role For Nonenzymatic Glycation

Glycation is the nonenzymatic reaction of glucose, a-oxoaldehydes, and other sac-charide derivatives with proteins, nucleotides, and lipids, with formation of early gly-cation adducts (fructosamines) and advanced glycation end products (AGE). Formation of some AGE, i.e., pentosidine and E- carboxymethyl -lysine, combines both glycation and oxidative steps in a process termed glycooxidation. In the last several years, the role for glycation glycoxidation in diabetic complications including...

Differential Diagnosis

In focal neuropathy, occurring in patients with diabetes, a neuropathy of another origin must always be excluded. In patients with ophthalmoplegia, preservation of pupillary function in a nearly complete third nerve palsy strongly suggests a diabetic origin, however, even in such cases, it is wiser to perform a noninvasive investigation of the area. Magnetic resonance angiography will permit exclusion of a compressive lesion of the third nerve by a large aneurysm of the carotid artery within...

Secretomotor Function

Kennedy et al. (26) has done extensive studies on sudomotor innervation in human and experiment diabetic neuropathy. Most of the experimental studies were done on experimental diabetes in the mouse. They provided detailed ultrastructural studies of the mouse sweat gland (27). Many nerve fibers are entwined with the secretory tubule and contain accumulations of round, clear vesicles, some microtubules, but apparently no neurofilaments. Cholinesterase is found in the clefts between nerve fibers...

Regulation Of Blood Pressure

The maintenance of postural normotension without an excessive heart rate increment requires an adequate blood volume and the integration of reflex and humoral systems in several key vascular beds. These include striated muscle, splanchnic-mesenteric, and cerebrovascular beds. An adequate blood volume is essential. Hypovolemia regularly causes OH, even if vascular reflexes are intact. Hypovolemia can also be relative. Adrenergic den-ervation decreases vascular tone and increases vascular...

Ssr

Skin potential recordings can be used to detect sympathetic sudomotor deficit in the peripheral neuropathies and central autonomic disorders (57,58). The recording electrodes are commonly electrode pairs 1 cm in diameter applied to the dorsal and ventral surfaces of the foot, the hand, or thigh. The stimulus might be an inspiratory gasp, a cough, a loud noise, or an electric shock. The sources of the skin potential are the sweat gland and the epidermis (59). A reasonable interpretation of...

Introduction

Apoptosis or programmed cell death (PCD) is essential for the normal functioning and survival of most cells including those in the peripheral nervous system (PNS). The morphological appearance of apoptosis, the severity of cell death, and the mechanism of cell death might vary between different cell types in the PNS and between different mammalian models of diabetes. However, most cells show evidence of mitochondrial (Mt) From Contemporary Diabetes Diabetic Neuropathy Clinical Management,...

Clinical Classification Of Diabetic Polyneuropathy

Although clinical classification of the various syndromes of diabetic peripheral neuropathy are often difficult because of the very considerable overlap in the mixture of clinical features, attempts at classification stimulate thought as to the etiology of the various syndromes and also assist in the planning of management strategy for the patient. Watkins and Edmonds (9) have suggested a classification for diabetic polyneuropathy based on the natural history of the various syndromes, which...

Sonic Hedgehog And Diabetic Neuropathy

Mechanism Diabetic Neuropathy

The hedgehog proteins are a highly homologous family of proteins that are widely expressed during development. There are three known mammalian homologues sonic (Shh), desert (Dhh), and indian (Ihh). Treatment of the streptozotocin (STZ) rat model of diabetes with a fusion protein containing human recombinant Shh and rat immunoglobin G (Shh-IgG) ameliorates a range of diabetes-induced functional and structural disorders of the peripheral nerve. For example, motor and sensory nerve conduction...

Assessment Of Neuropathic Pain

It is important to emphasize the difficulties in the description and in the assessment of painful symptoms. Pain is a very personal experience and there is marked variation in the description of symptoms between patients with similar pathological lesions. This has important implications for trials of therapies for neuropathy and, as stated by Huskison (11) pain is a personal psychological experience and an observer can play no legitimate part in its direct management. Thus, any trial of...

Neurofilament

NF, consisting of heavy, medium, and light subunits, form the major structural lattice of axon. The function of the neurofilaments (NF) is not clear, but abnormal phosphorylation of these proteins is associated with neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson disease, Alzheimer disease, and diabetes (58,59). In diabetes, stress-activated protein kinases are thought to be involved in their aberrant phosphorylation (60,61). Further, abnormal NF accumulation was...

Therapies Targeted To Metabolic Pathways

Note The aldose reductase inhibitors are discussed elsewhere (see Chapter 18). Antioxidants Hyperglycemia has been shown in a number of studies to cause oxidative stress in tissues that are susceptible to the complications of diabetes, including peripheral nerves. In turn, the oxidative stress leads to the generation of free radicals that can attack the lipids, proteins, and nucleic acids of the affected tissues directly, compromising physiological function. The end result is the loss of axons...

Diabetic Foot Formalin

Eaton SE, Harris ND, Rajbhandarim SM, et al. Spinal-cord involvement in diabetic peripheral neuropathy. Lancet 2001 358 35-36. 2. Diamond MC, Scheibel AB, Elson LM. The Human Brain Coloring Book. Harper Collins, New York, NY, 1985. 3. Harper AA, Lawson SN. Conduction velocity is related to morphological cell type in rat dorsal root ganglion neurons. J Physiol 1985 359 31-46. 4. Lee KH, Chung K, Chung JM, Coggeshall RE. Correlation of cell body size, axon size, and signal conduction velocity...

Implications For Future Epidemiological Research

Research on the epidemiology of diabetic neuropathy is at an earlier stage in comparison with other diabetic complications. Considerable advances would occur in this field if standardized definitions were developed and used in multiple investigations, although care should be taken to avoid protocols that would be burdensome to study participants, because these would increase the likelihood of bias because of unac-ceptably low participation rates. Also, measurement methods should be used which...

Constipation

Constipation and the use of laxatives are relatively common in patients with diabetes mellitus 79 but the mechanism of constipation remains unclear. Epidemiological studies in community-based practices suggest that physicians should not immediately assume that GI symptoms in patients with diabetes mellitus represent a complication of diabetes mellitus 80 . Diabetic autonomic neuropathy may be implicated in some patients, but other factors might also be important. For instance, evacuatory...

References

Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycemic damage. Nature 2000 404 787-790. 2. Smith AG, Ramachandran P, Tripp S, Singleton JR. Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology 2001 13 1701-1704. 3. Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003 60 108-111....

Candidate Genes

A number of genetic models have been proposed for the interaction of the diabetic milieu with genetic background of the individual. These include models in which the genetic factors modify the progression of the disease or possibly glycemic control 18,19 . Clearly, this would explain why some patients with well-controlled diabetes still develop complications, wheras others with poorly controlled diabetes escape any complications. There is a wide-spectrum in the incidence of microvascular...

Role For Vascular Vs Nonvascular Mechanisms

Over past several years, the importance of vascular vs nonvascular mechanisms in the pathogenesis of PDN remained a subject of debate. The key role of reduced NBF and resulting endoneurial hypoxia in diabetes-associated nerve conduction deficit appears to be supported by the findings with a variety of vasodilators for example, the -adrenoceptor antagonist prazosin 20 , the K ATP channel openers, celikalim and WAY135201 21 , the AT-converting enzyme ACE inhibitor enalapril, and the AT II...

Techniques To Assess Microvascular Dysfunction And Their Limitations

Endothelial dysfunction, assessed at the macrocirculation, has been proven as an early marker of vascular complications in several diseases, including diabetes, dyslipi-demia, and hypertension. The development of techniques capable to measure the skin blood flow has also enabled the study of the vascular reactivity at the microcirculation level. More specifically, the noninvasive measurement of cutaneous blood perfusion can be performed by the laser Doppler. Currently, laser Doppler flowmetry...

N

NBF, see Nerve blood flow NCV, see Nerve conduction velocity NDF, see Neuropathy Disability Score Nerve biopsy, neuropathy diagnostics, 284 Nerve blood flow NBF diabetic neuropathy role, 70-72 reduction in neuropathy, 70, 71 Nerve conduction velocity NCV , neuropathy diagnostics, 280-282 Nerve growth factor NGF diabetic neuropathy expression, 238 neuropathy protection, 43 streptozotocin-induced diabetes studies, 160 therapeutic prospects, 329, 330 Neurofilament deficient mouse studies, 59, 60...

Epidermal Innervation In Clinical Trials

Skin biopsy with determination of epidermal nerve fiber density lends itself to application as an outcome measure in regenerative and longitudinal studies. The technique offers the advantage over NCVs that it focuses on a larger subset of nerve fibers than nerve conduction testing and unmyelinated nerve fibers appear to be a more sensitive measure of neuropathy than large myelinated nerve fibers. Several small studies have used serial skin biopsies as an outcome measure. In a trial of...

Parp Activation

Increased oxidative stress, presumably from polyol pathway activity, AGE and its interaction with RAGE, PKC activation, and hyperactivity of mitochondrial respiratory chain, damages lipids, proteins, and DNA 49 . DNA strand breaks activate PARP, which is an enzyme that transfers ADP-ribose from NAD to nuclear proteins as part of the DNA repair process 50 . However, overactivation of PARP has deleterious consequences, including the activation of the proinflammatory transcription factors NF-kB...

Info

The ALR2 gene is localized on chromosome 7q35 AKR1B1, NM001628 45 . Pseudogenes have also been found on other chromosomes 46 . The gene extends more than 18 kb and contains 10 exons that code for a 1384 bp mRNA. The basal promoter activity is located between position -192 and 31. Several ds-regulatory elements have been isolated and point mutations in certain sequences such as the TATTTA reduced promoter activity to 35 of the wild-type DNA. The basal promoter region contains a consensus...

Extrinsic Pcd Pathway

The receptor-linked pathway is known as the extrinsic pathway and this pathway requires binding of a ligand to a death receptor on the cell surface 4 . In this system, tumor necrosis factor TNF and Fas ligand FasL bind to their cell surface death receptors, TNF receptor type 1 and Fas receptor, respectively. Once activated, these receptors recruit the signal-producing moieties TNF receptor type 1-associated death domain, Fas-associated death domain 4 , and caspase-8 forming an oligomeric...

Conclusion Linking Microvessels Diabetes And Neuropathy

Compelling experimental and human work, as summarized here, has highlighted the intimate connection between microangiopathy and diabetic polyneuropathy. Epidemiological work has similarly suggested that patients with macrovascular risk factors are at greater risk of developing polyneuropathy. A number of experimental and human studies have suggested that there is a direct cause and effect relationship between diabetic microangiopathy and polyneuropathy. These have identified reduced nerve blood...

Selection Of Biopsy Site And Processing Technique

Antibody Pgp Skin

Generally, skin biopsies are very well tolerated and result in negligible scarring in individuals without a predilection to keloid formation. Discoloration at the biopsy site tends to be more prominent among darker pigmented individuals. The rate of infection even among neuropathic populations is small, approximately 1 500. Biopsy sites Fig. 1. Example of innervation of dermal appendages. Examples of dermal appendages stained with PGP 9.5. A Sweat gland from a normal control that is robustly...

Symmetrical Neuropathies

Chronic Distal Symmetrical Neuropathy This is the most common neuropathic syndrome and what is meant in clinical practice by the phrase diabetic neuropathy. Clinical manifestations 14 and measurements 15,16 of distal symmetrical neuropathy have recently been reviewed. There is a length-related pattern of sensory loss, with sensory symptoms starting in the toes and then extending to involve the feet and legs in a stocking distribution. In more severe cases, there is often upper limb involvement,...

Treatment Of Painful Diabetic Neuropathy

Under this section the many different approaches to the management of symptoms in those with distal sensory neuropathy will be considered. First, the role of blood glucose control in the prevention and management of painful neuropathy will be discussed followed by a description of the various pharmacological treatments that have been proposed. This section will be divided into those purely symptomatic treatments and those symptoms that target the underlying pathogenesis of neuropathy and might...

Gastroduodenal Dysfunction The Gastroparesis Syndrome

Ballondilatation Pylorus

Diabetic gastroparesis is an electromechanical motility disorder that in many instances involves not only the stomach, but also the upper small bowel. The molecular pathophysiology of diabetic gastroparesis is unknown. In fact, a variety of pathogenetic factors may be implicated in most patients. Animal studies point to a defect in the enteric nervous system characterized by a loss of nitric oxide signals from nerves to gut smooth muscle 18,19 . Interstitial cells of Cajal might also be...

Contributors

Misha-Miroslav Backonja Department of Neurology, School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI Geert Jan Biessels Department of Neurology of the Rudolf Magnus Institute for Neuroscience, University Medical Centre, Utrecht, The Netherlands Andrew J. M. Boulton Department of Medicine, Manchester Royal Infirmary, Manchester, UK Edward J. Boyko VA Puget Sound Healthcare System, Seattle, WA Rebecca C. Burnand Faculty of Life Sciences, University of Manchester,...

Structural Abnormalities In Type And Type

Diabetic Neuropathy Myelinated Axon

One of the earliest detectable structural changes in sensory myelinated fibers is the conspicuous enlargement or swelling of the nodal and paranodal axon, which correlates with the early Na K -ATPase defect and increased axonal Na J 30,33 and is reversible after metabolic corrections. This abnormality is less frequent in early type 2 DPN in the BBZDR Wor-rat, probably related to the milder defect in the Na K -ATPase activity 31,56 . Other early ultrastructural abnormalities observed in sensory...

Asymmetrical Neuropathies

The diabetic state can also affect single nerves mononeuropathy , multiple nerves mononeuropathy multiplex , or groups of nerve roots. These asymmetrical or focal neuropathies have a relatively rapid onset, and complete recovery is usual. This contrasts with chronic distal symmetrical neuropathy, where there is usually no improvement in symptoms 5 years after onset 36 . Unlike chronic distal symmetrical neuropathy they are often unrelated to the presence of other diabetic complications 9,15,16...

Therapies For Microvascular Insufficiency

Although it is clear that there are significant alterations of blood vessels in diabetes, data thus far has been conflicting whether neuropathy promotes the changes in the microvasculature or whether it is the changes in the microvessels of the nerves that lead to neuropathy. Whatever the case, evidence is growing that re-establishing more normal patterns of blood flow to the nerves results in improved neurological function. Protein kinase C PKC and diacylglycerol DAG are intracellular...

Gvp

Axonal Reflex Histamine

The vasodilatory response to the iontophoresis of acetylcholine hatched bars and sodium nitroprusside black bars at the foot level. The response to acetylcholine endothelium dependent vasodilation was equally reduced in the diabetic neuropathic patients with a history of foot ulceration DN group , the patients with both neuropathy and peripheral vascular disease DI , and the patients with Charcot neuroarthropathy DA when compared with nonneuropathic diabetic patients D and healthy...

Nonenzymatic Glycation

In diabetic animals and patients increased advanced glycation end products AGE covalently attach to intracellular, plasma and extracellular matrix proteins in the nerve, and other tissues 37,38 . It has been postulated that such modifications might affect neural metabolism, axonal transport, and tissue repair, thus enhancing neural degeneration and impairing neural regeneration. The strongest evidence in support of this model is that administration of aminoguanidine, an AGE inhibitor,...

Erectile Dysfunction

Neuroendocrine Control Penile Erection

Erectile dysfunction ED , defined as the consistent or recurrent inability of a man to attain and or maintain a penile erection sufficient for sexual activity 15 , is one of the most common sexual dysfunctions in men. ED is more common with advancing age, and since the aged population will increase, its prevalence will continue to rise 16 . Diabetes mellitus is the most frequent organic cause for ED, the onset of which starts about 15 years earlier in the diabetic than in the nondiabetic...

Acute Painful Neuropathies

These are transient neuropathic syndromes characterized by an acute onset of pain in the lower limbs. Acute neuropathies present in a symmetrical fashion are relatively uncommon. Pain is invariably present and is usually distressing to the patient, and can sometimes be incapacitating. There are two distinct syndromes, the first of which occurs within the context of poor glycemic control, and the second with rapid improvements in metabolic control 43 . Acute Painful Neuropathy of Poor Glycemic...

Underlying Metabolic Abnormalities In Type And Type

Growth And Metabolic Abnormalities

Several hyperglycemia-induced pathways have been invoked as the pathogenetic basis for DPN, such as 1. Activation of the polyol-pathway resulting in redox imbalances and perturbation of myoinositol and organic osmolyte imbalances 17-19 . 2. Nonenzymatic glycation yielding advanced glycation end products 20 . 3. Perturbations of neurotrophic homeostasis affecting particularly the nerve growth factor NGF and insulin-like growth factor IGF systems Fig. 1 21-24 . Fig. 1. Scheme of pathogenetic...

Anticonvulsant Drugs

Although the anticonvulsants, including carbamazepine, phenytoin, and gabapentin, have been effective in treating painful diabetic neuropathy see Chapter 21 , newer classes of anticonvulsants have shown surprising promise in treating both the symptomatic pain of diabetic neuropathy and the neuronal deficits. Topiramate is a fructose analog that was initially examined because of its antidiabetic possibilities. Although it is an anticonvulsant used in complex partial seizures, topira-mate was...

Charcot Neuroarthropathy

Common Feet Deformities

Charcot neuroarthropathy is a noninfectious progression of joint destruction characterized by pathological fractures and joint dislocations. Although it was initially described by Musgrave in 1704, its name was attributed to J.M. Charcot in 1868 116 . The disease involves joint destruction of accompanying common diseases that manifest with peripheral neuropathy, such as leprosy, tertiary syphilis, chronic alcoholism, and spina bifida 117 . Diabetes mellitus is currently the primary cause of...

Correlation Between Epidermal Nerve And Sural Nerve

Diabetes Cutaneous Nerve Fibers

Twenty six patients with neuropathic complaints had sural nerve morphometry and determination of epidermal nerve fiber density at the distal part of the leg 20 . The intraepidermal nerve fiber IENF density correlated with the densities of total myelinated fibers within the sural nerve r 0.57, p 0.0011 , small myelinated r 0.53, p 0.029 , and large myelinated fibers r 0.49, p 0.0054 . There was a trend toward an association between intraepidermal nerve fiber density and sural nerve unmyelinated...

Vasoregulation Of Somatic Nerve Fibers

Vasoregulation

An early and consistent finding is impaired vasoregulation of peripheral nerve trunk. Nerve blood flow to peripheral nerve is reduced to about 50 of normal. The reduction occurs early and is sustained. In a recent review 1 of studies of peripheral nerve blood flow in experimental diabetic neuropathy, a reduction was demonstrated in 19 21 research programs Table 1 and typically on multiple occasions. The two laboratories that failed to demonstrate this deficit had methodological problems such as...

Diabetic Neuropathy

Polyol Pathway Diabetic Neuropathy

Experimental studies have provided multiple mechanisms for the development of diabetic neuropathy, yet very few findings have been replicated in patients. Hyperglycemia mediated nerve damage may begin very early even prior to overt diabetes as evidenced by several recent studies in patients with impaired glucose tolerance. Polyol pathway abnormalities have been exhaustively explored in animals, but studies in man are limited and inconsistent and hence not surprisingly, clinical trials with...

Nerve Axon Reflex-related

Axon Reflex Sweating

ICapillary blood flow Endoneurial hypoxia Fig. 1. New concepts in the pathogenesis of diabetic neuropathy. Fig. 2. Expression of eNOS in patients with diabetic neuropathy black columns , patients with both diabetic neuropathy and peripheral vascular disease hatched columns and healthy subjects white columns . The expression of eNOS was reduced in both the diabetic groups compared with the healthy subjects data from ref. 18 . Fig. 2. Expression of eNOS in patients with diabetic neuropathy black...

Fecal Incontinence

Fecal incontinence is a challenging clinical condition particularly in elderly diabetics. It has been estimated that upto one-fifth of patients with diabetes have fecal incontinence, although prevalences depend on criteria of incontinence applied. The incidence of fecal incontinence in diabetics appears to correlate with duration of the disease 90 . Incontinence is probably multifactorial and involves age-related changes, diabetic neuropathy, multimorbidity, and polymedication 91 . However,...

Diabetic Amyotrophy And Mononeuropathies In Persons With Diabetes

There have been no prospective, population-based studies of diabetic amyotrophy and mononeuropathies in subjects with diabetes. However, some prevalence figures for these types of neuropathy can be derived from a few cross-sectional studies. In a cross-sectional survey based in Rochester, Minnesota, asymptomatic carpal tunnel syndrome CTS was found in 22 of those with type 1 diabetes and 29 of those with type 2 diabetes, whereas the corresponding prevalence for symptomatic cases was 11 and 6 ,...

Diabetic Sudomotor Disorders

Sudomotor symptoms are common, but do not usually command much attention. Initially, there may be hyperhidrosis of the feet associated with coldness I can't keep my feet warm . This is followed by anhidrosis and vasomotor alterations, which can be variable, with venous congestion and a purple discoloration being common. Some patients will have alternating warming and cooling. Infrequently, widespread anhidro-sis results in heat intolerance. In these patients, a high ambient temperature and...

Autonomic Regulation Of Cardiovascular Function

The best known manifestation of early dysautonomia in human diabetic neuropathy is a loss of cardiovagal function 7 . Similar abnormalities have been described after several months of diabetes in experimental diabetic neuropathy EDN . In a study of Yucatan miniature pigs, blood pressure BP and heart rate where recorded telemetrically 8 . After 3 months of diabetes induced with streptozotocin STZ , there was a marked reduction in respiratory sinus arrhythmia. Beyond 3 months, the impairment of...

Lowpa In Vivo Studies On Receptor Pharmacology

Comparison of distal sympathetic with vagal function in diabetic neuropathy. Muscle Nerve 1986 9 592-596. 2. Anonymous. Consensus statement on the definition of orthostatic hypotension, pure auto-nomic failure, and multiple system atrophy. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Neurology 1996 46 1470. 3. Low PA, Denq JC, Opfer-Gehrking TL, Dyck PJ, O'Brien PC, Slezak JM. Effect of age and gender on...

Nzv

CAD, see Coronary artery disease Calcitonin gene-related peptide CGRP spinal cord axon studies in diabetes, 173, 179 vasodilation, 209 Calcium flux, oxidative stress and diabetic neuropathy pathogenesis, 82 CAN, see Cardiovascular autonomic neuropathy Capsaicin, painful neuropathy management, 360 Cardiac adrenergic innervation, diabetic autonomic neuropathy, 156, 157 Cardiovascular autonomic neuropathy CAN clinical implications anesthesia and surgery risks, 397 cardiac denervation syndrome,...

Cd Cd Cd Ep P Ep

Neuro Ncv60

A Localization of carboxymethyl lysine, receptor for advanced glycation end products, activated nuclear factor-KBp65, and interleukin-6 antigens in epineurial vessels top , perineurium middle , and endoneurial vessels bottom of sural nerve biopsies from a representative patient with diabetes mellitus and Charcot-Marie-Tooth disease Scale bars 100 im . B Quantification of staining intensities of epineurial vessels, perineurium, and endoneurial vessels in nondiabetic n 8 and diabetic n 10...

Qsart

QSART evaluates postganglionic sudomotor function. It probably evaluates the distal ends of the postganglionic axon 50 . The test is quantitative, reproducible, and noninvasive with a coefficient of variation of 8 51 . QSWEAT is the commercial counterpart, modeled after the Mayo Clinic system. The neural pathway consists of an axon reflex mediated by the postganglionic sympathetic sudomotor axon. The axon terminal is activated by acetylcholine. The impulse travels antidromically, reaches a...

Ncv

The principal factors deemed to influence NCV are the integrity and degree of myelination of the largest diameter fibres the mean axonal cross-sectional diameter the representative internodal distance, and the distribution of nodal ion channels. Although demyelination can produce a profound deficit in NCV, it has been proposed to play only a minor role in slowing of NCV in diabetic peripheral neuropathy DPN 30 . It has been suggested that the initial structural deficit responsible for NCV...

Diabetic Oh

OH is relatively common in patients with diabetic neuropathy 10,15,16 , although the frequency reflects referral bias. OH was found in 43 of 16 patients 10 and 26 of 73 patients 1 . Mulder et al. 17 found OH in 18 of 103 unselected patients with diabetes of whom 43 had polyneuropathy. Veglio et al. 16 reported orthostatic intolerance in 34 of 221 patients with NIDDM patients. In some studies clinical failure is very uncommon. For instance, Young et al. 18 in a study of teenagers, did not find...

Macrovascular Disease And Diabetes An Overview

Both type 1 and type 2 diabetes are powerful and independent risk factors for coronary artery disease CAD , stroke, and peripheral artery disease. More specifically, the Framingham study showed that type 2 diabetes is associated with approximately a twofold increase in CAD in men and a fourfold increase in women 41 . It is also known that patients with diabetes have the same risk of acute myocardial infarction than patients without diabetes with a history of previous myocardial infarction, thus...

Pathophysiology Of Microvascular Disease And Endothelial Dysfunction In Diabetes

Pathophysiology Diabetic Polyneuropathy

Although microvascular diabetic complications have been well-characterized there is still uncertainty regarding the mechanisms that lead to their development. In the past two main pathogenic hypotheses have been proposed the metabolic hypothesis and the hypoxic hypothesis 11,12 . According to the metabolic hypothesis, hyperglycemia is directly responsible of end-organ damage and development of complications through the activation of the polyol pathway. On the other hand, according to the...

Functional Anatomy

Anatomy Schematic Diagrams Leg

It might be helpful if an overview of the anatomy of the spinal cord and associated structures that is a distillation of more detailed texts is provided first see ref. 2 . The spinal cord, which is divided into 31 segments, is ensheathed by the spinal canal that is formed by the bodies, pedicles, and spinous processes of individual vertebra. Each spinal segment 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal gives rise to a pair of spinal nerves that are joined to their segments by...

Treatment Of Nocturnal Hypertension

Normal subjects have a diurnal variation in BP, with lower nocturnal BP. Patients with neurogenic OH have nocturnal hypertension. To minimize the problems of nocturnal hypertension, pressor medications should not be taken after 6 PM. The head of the bed should be elevated, resulting in lower intracranial BP. A nighttime snack with a glass of fluids not coffee or tea results in some postprandial hypotension, and can be used to increase fluid intake and decrease nocturnal hypertension. Patients...

Autonomic Ganglia

Prominent physiological and less dramatic pathological changes are present in auto-nomic ganglia of DAN. There is a significant reduction in blood flow in autonomic ganglia such as superior cervical ganglion 32,33 . This reduction by about 50 is present as early as 1 week and is persistent over 24 weeks 4 . Glucose uptake was reduced to 30 of control values in superior cervical ganglion in rats with DAN. a-Lipoic acid supplementation had no effect on glucose uptake in normal nerves at any dose,...

Clinical Examination And Screening Techniques To Identify The Patient At Risk Of Foot Ulceration

Foot Ulcer Debridement

It is well-known that prevention remains the best means of averting the potentially devastating results of diabetic foot complications. It has been estimated that up to 80 of diabetic foot ulcers are preventable 70 . Accordingly, routine clinical examination to identify those patients at risk for ulceration has been advocated 71 . This involves a simple but thorough history and clinical examination consisting of a basic examination of the foot to include vascular, neurological, dermatological,...

Cranial Diabetic Neuropathy

Oculomotor nerve palsies are the most common if not the only cranial neuropathy observed in patients with diabetes. Ogle in 1866, was the first author to mention the occurrence of diabetic ophthalmoplegia 3 . In 1905, Dieulafoy published a series of 58 personal cases, in which most of the clinical characteristics of diabetic ophthalmoplegia were described 4 . In 1935, Waite and Beetham 5 performed the first epidemiological study on the subject in which they compared the occurrence of oculomotor...

Clinical Deficits

Michigan Diabetic Neuropathy Score

A number of scoring systems have been proposed to quantify clinically neurological deficits and hence, define the presence and severity of neuropathy. This approach was originally pioneered by Dyck et al. 15 in the Mayo Clinic who described the neuropathy disability score Mayo NDS . A comprehensive evaluation of muscular strength in the face, torso and extremities, reflexes of the upper and lower extremities and sensation to pain, vibration, and joint position at the index finger and great toe...

Diabetic Foot Ulceration

Diabetic Foot Ulcer Process Formation

The risk factors for diabetic foot ulceration can be categorized into three distinct groups pathophysiological, anatomic deformities, and environmental influences. The pathophysiological changes, which occur at the biomolecular level lead to changes that result in the development of peripheral sensory neuropathy, peripheral vascular disease, and a compromised immune system with alteration in wound healing capabilities. The second group with anatomic deformities are largely the result of motor...

Diabetesinduced Neuropathology

While there are earlier reports of spinal cord lesions associated with diabetes mellitus refs. 5-7 , the publication of a series of key 8-12 and other 13-16 neuropathologi-cal studies in the latter half of the 20th century established the histological nature of this injury. These reports helped promote the concept that myelopathy is a part of the diabetic process and remain the definitive neuropathological studies. Unlike myelopathy, the existence of peripheral neuropathy and radiculopathy is...

Microangiopathy Diabetes And The Peripheral Nervous System Experimental Studies

Neuropathy Peripheral Nervous System

Tuck and colleagues 22 initially reported that experimental diabetes of rats was associated with a decline of sciatic nerve blood flow and endoneurial hypoxia. Several other laboratories have reported similar findings and a variety of interventions have been reported to both correct nerve blood flow and diabetic electrophysiological abnormalities in tandem see review 2 . A large number of such studies through their findings have consequently implied that reductions in nerve blood flow initiate...

Changes In Brain

Great advances have been made during last couple of decades in our understanding of the pathophysiology of neuropathic pain, as a result of basic scientific findings of the pathological and biochemical changes in the peripheral and central nervous system. The neuronal changes that take place at the level of human brain as the consequence of peripheral neuronal injury, such as in case of PDN, lead to the processes that maintain neuropathic pain known as central sensitization. Examination of the...

Experimental Erectile Dysfunction

Experimental erectile dysfunction in experimental diabetes and aging has been studied in the rat 40-42 . Rat studies typically consist a measurement of intracavernous pressure in response to electrical stimulation of the cavernous nerve in normal and diabetic rats 43 . The pathophysiology of erectile dysfunction in DAN appears to mimic the human condition wherein it is vasculogenic resulting in engorgement of corpora cavernosa and is because of a deficiency of nitric oxide 40,44-46 . In the...

Gustatory Sweating

Gustatory sweating was first linked to diabetes mellitus by Watkins 75 , and is now known to occur quite commonly in patients with either diabetic nephropathy or neuropathy 76 . The syndrome consists of localized hyperhidrosis of the face during meals. The mechanism of gustatory sweating is not proven, but is considered to be because of sympathetic postganglionic denervation followed by aberrant reinnervation by parasympathetic fibers. It is suggested that sympathetic cholinergic fibers to...

Referenfces

The epidemiology of diabetic neuropathy. Diabetes Rev 1999 7 245-252. 2. Tesfaye S, Stephens L, Stephenson J, et al. The prevalence of diabetic neuropathy and its relation to glycaemic control and potential risk factors the EURODIAB IDDM Complications Study. Diabetologia 1996 39 1377-1384. 3. Young MJ, Boulton AJM, Macleod AF, Williams DRR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population....

The Polyol Pathway

The polyol pathway is a glucose shunt that diverts excess glucose to form fructose. AR is the first and rate-limiting enzyme of the pathway. It reduces glucose to sorbitol, and in the process its cofactor NADPH is oxidized to NADP. Sorbitol dehydrogenase SDH then converts sorbitol to fructose, whereas its cofactor NAD is converted to NADH. The polyol pathway was first recognized as a key factor in the development of diabetic cataracts, and soon afterwards, it was found to be involved in...

Patterns Of Anhidrosis In Diabetic Neuropathy

There are a number of patterns of anhidrosis in diabetic neuropathy. A full appreciation of these patterns requires the administration of the thermoregulatory sweat test, a method that is not under widespread clinical use. Several well characterized patterns are described. Perhaps, the most common pattern of anhidrosis is distal anhidrosis. The burning feet syndrome is perhaps the most common presentation of diabetic neuropathy. These patients have distal involvement with burning, prickling,...

Acute Nerve Ischemia

It is important when considering some types of neuropathy in diabetes to ask whether ischemia plays a role. Peripheral nerve trunks are resistant to acute ischemia in part because of their rich anastamotic vascular supply and their limited metabolic demands. Several models of experimental ischemic neuropathy have been developed ranging from multiple arterial ligation, embolization by microspheres or other agents, and the topical application of the potent vasoconstrictor endothelin 3,41-50 ....