Epidemiology

Difficulties in accurate estimates of the prevalence of CAN reflect a number of factors including variations in the populations studied, the source of the patients within these populations, individual patient characteristics, choice of test utilized, and the diagnostic criteria. In 1988, in order to reduce some of these variabilities, the San Antonio Conference on Diabetic Neuropathy made a number of recommendations, including the choice of tests to be performed as well as recommending that...

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...

Summary

Ancient records of diabetes generally contain no reference to its complications involving the nervous system. A few rare exceptions describing autonomic and painful neuropathies are all coming from the Orient. It was not until the 18th century that Western physicians started studying diabetes and its complications. Eventually, the works of the 19th century (de Calvi, Pavy) clearly established the link between diabetes mellitus and diabetic neuropathies. The epochal discovery of insulin in 1921...

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...

Growth Factors

A deficiency of insulin like growth factors (IGF's) has been proposed to lead to cell death. Neuroaxonal dystrophy occurs in the nerve terminals of the prevertebral sympathetic ganglia and ileal mesenteric nerves of the streptozotocin (STZ)-diabetic and biobreeding Worcester rat, and has been related to hyperglycemia and a deficiency of circulating IGF-I levels. In contrast, although the Zucker diabetic fatty rat is hyperglycemic it does not develop neuroaxonal dystrophy because it is claimed...

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...

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...

Management

There is no therapy currently available for the treatment of CAN. Therefore, treatment mostly focuses upon management of a number of modifiable risk factors, which can significantly reduce the risk of developing CAN. In the European Diabetes Prospective Complications Study (EURODIAB), which enrolled 1172 patients with type 1 diabetes, the incidence of neuropathy was associated with a poor glycemic control, elevated triglyceride levels, increased body-mass index, smoking, and hypertension (141)....

Role For Nonenzymatic Glycation

Glycation is the nonenzymatic reaction of glucose, a-oxoaldehydes, and other saccharide derivatives with proteins, nucleotides, and lipids, with formation of early glycation 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...

Vasoregulation Of Somatic Nerve Fibers

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...

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...

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...

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...

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...

Correlation Between Epidermal Nerve And Sural Nerve

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...

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...

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...

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 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 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...

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...

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...

Type 1 Dm Vs Type 2 Dm

There is very little data for a direct comparison of the incidence and prevalence of neuropathy in the two major types of diabetes. Comparison between studies is very difficult because of the different methods used for defining neuropathy. The DCCT, which studied subjects with type 1 diabetes, showed after 5 years follow-up that abnormal nerve conduction in at least two nerves occurred in 15-30 of subjects that were tightly controlled, and in 40-52 of controls (37). In the UKPDS, which studied...

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...

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...

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...

Structural Abnormalities In Type 1 And Type 2

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...

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...

C

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...

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...

Structuralfunctional Correlations

From the above it is clear that the early defects in NCV are caused by metabolic abnormalities, most noticeably the early Na+ K+-ATPase defect. The type 1 diabetes model shows a more severe defect, which is likely to cause subthreshold initial Na+ currents at the node resulting in a conduction block of large fast conducting myelinated fibers (52,53). This would explain the early steep decline in NCV in this model. The early reversible NCV defect is associated with reversible paranodal and nodal...

Principles Of Arterial Reconstruction

Patients with diabetes at risk of lower limb amputation because of the presence of a peripheral vascular disease are a growing population because of the higher prevalence of diabetes and to the longer life expectancy of the general population. There is increasing evidence that distal arterial revascularization is effective in preventing major amputations in the population with diabetes (51). The indications for limb revascularization are disabling claudication (not common in patients with...

Treatment For Periods Of Orthostatic Decompensation

Patients who have restricted autonomic neuropathy and associated postural tachycardia have periods of orthostatic decompensation. Patients with generalized autonomic failure also have episodes of apparent decompensation when they have greater OH or less response to pressor agents. These patients need to be evaluated for a cause of decompensation. The causes include fluid deficit, hypokalemia, anemia, deconditioning related to a recent period of recumbency, and another illness (including pump...

Introduction

Complications involving the foot are common in patients with diabetes mellitus. Manifestations of these complications range from the simple to more complex entities, which are limb or even life threatening. The treatment of these complications ranges from simple office-based interventions to prolonged hospitalizations. Foot pathology remains the leading diabetic complication requiring hospitalization (1). The incidence of diabetes in the general population is expected to rise as well as the...

References

Dvornik D, Simard-Duquesne N, Krami M, et al. Polyol accumulation in galactosemic and diabetic rats control by an aldose reductase inhibitor. Science 1973 182 1146-1148. 2. Tomlinson DR, Willars GB, Carrington AL. Aldose reductase inhibitors and diabetic complications. Pharmacol Ther 1992 54 151-194. 3. Pfeifer MA, Schumer MP, Gelber DA. Aldose reductase inhibitors the end of an era or the need for different trial designs Diabetes 1997 46(Suppl 2) S82-S89. 4. Dyck PJ, O'Brian PC. Meaningful...

B

Baroreflex sensitivity, regulation in diabetic autonomic neuropathy, 155, 156 BB Wor rat metabolic abnormalities, 134-136 myelinated fiber function, 136-139 structural abnormalities myelinated sensory fibers, 141, 143 nodal and paranodal changes, 143, 144 unmyelinated fiber pathology, 144, 145 structure-function correlations myelinated fibers, 145, 146 unmyelinated fibers, 146 type I diabetes polyneuropathy model, 134 unmyelinated fiber function, 139-141 BBZDR Wor rat metabolic abnormalities,...

S

Schwann cell, apoptosis in diabetic neuropathy, 124, 126 SDH, see Sorbitol dehydrogenase SDI-58, streptozotocin-induced diabetes studies, 160 Secromotor function, diabetic autonomic neuropathy findings, 158, 159 Selective serotonin reuptake inhibitors, painful neuropathy management, 359 Semmes-Weinstein monofilament test, diabetic foot evaluation, 485 Sensory nerve action potential (SNAP), neuropathy diagnostics, 282 Shh, see Sonic hedgehog Sildenafil erectile dysfunction management in...

V

Vacuum devices, erectile dysfunction management in diabetes, 467 Vardenafil, erectile dysfunction management in diabetes, 466 VAS, see Visual analog scale Vascular endothelial growth factor (VEGF) diabetic neuropathy pathogenesis, 41, 237, 238 therapeutic prospects, 327 Vasomax , see Phentolamine VEGF, see Vascular endothelial growth factor Viagra , see Sildenafil Vibration pressure threshold (VPT), foot ulcer risk assessment, 486 Visual analog scale (VAS), pain assessment, 354, 355 Vitamin E,...

Spinal Electrophysiology In Diabetes

Slowing of large motor and sensory fiber conduction velocity has long been recognized as an early indicator of neuropathy in the PNS (41,42) and these deficits are widely used to follow progression of neuropathy and assess efficacy of therapeutic interventions. In contrast, there have been relatively few evaluations of spinal electro-physiology in diabetic subjects and such measurements are rarely included in global assessments of neuropathy. Increased latencies, indicative of conduction...

L

Microvascular dysfunction assessment, 266 nerve blood flow, 209, 210, 219, 220 Laser Doppler perfusion imager (LDPI), microvascular dysfunction assessment, 266-268 LDF, see Laser Doppler flowmetry LDPI, see Laser Doppler perfusion imager Learning and memory, see Diabetic encephalopathy Levitra , see Vardenafil Lidocaine, painful neuropathy management, 361 y-Linolenic acid, antioxidant therapy in diabetic antioxidant therapy in diabetic neuropathy, 324, 325 management, 402, 403 painful...

Soe

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,...

Conclusion

Changes in the micro- and macrocirculation, both anatomical and functional, contribute to the development of diabetic neuropathy. On the other hand, the development of diabetic neuropathy also affects the vasodilatory capacity of the microcirculation and can interfere with the clinical presentation of peripheral obstructive arterial disease. Thus, the interaction between changes in the vasculature and peripheral nerves is bidirectional and results in changes in both blood flow and neuronal...

M

Magnetic resonance imaging (MRI) brain findings in diabetes, 194, 196 neuropathy diagnostics, 285 MAPK, see Mitogen-activated protein kinase Mcgill pain questionnaire (MPQ), pain assessment, 355 Megalin, sonic hedgehog receptor, 94 Mesenteric arterial function, diabetic autonomic neuropathy, 157 Metatropic glutamate receptors, neuroprotection, 123 Metoclopramide, gastroparesis management in diabetes, 441 Mexiletine, painful neuropathy management, 360 Microangiopathy blood flow of nerve trunks...

Esophageal Dysfunction

Autonomic neuropathy is the main pathogenetic suspect. Neuropathological esophageal abnormalities have been reported by Smith (8), who observed swelling, irregularity of caliber, and disruption of parasympathetic fibers in the esophageal wall and in the extrinsic trunks. The myenteric plexus appeared normal except for a lym-phocytic infiltration within the ganglia. Hyperglycemia might also be involved, it will be shown later for a number of motor gut disturbances. Esophageal motor dysfunction...

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...

Info

Local measurements of erythrocyte flux (LDF) made in patients with mild diabetic polyneuropathy before a sural nerve biopsy in comparison with patients without diabetes with other polyneuropathies or with vasculitic polyneuropathy. Note that patients with diabetes had trends toward higher flux whereas patients with vasculitis had significant reductions in local blood flow. One patient with a sural nerve that was treated with epinephrine had reduced flux whereas a patient with diabetes...

O

Octreotide, diarrhea management in diabetes, 444, 445 Opioids, painful neuropathy management, 360 Orthostatic hypotension blood pressure regulation, 414, 415 cardiovascular autonomic neuropathy, 397 clinical manifestations, 416, 418 definition, 413, 414 laboratory evaluation, 418, 419 management early morning orthostatic hypotension, 423 erythropoietin, 423, 424 fludrocortisone, 421, 422 hospital management, 422, 423 midodrine, 420, 421 nocturnal hypertension, 423 orthostatic decompensation,...

Contents

1 Historical Aspects of Diabetic 2 The Epidemiology of Diabetic Stephanie Wheeler, Nalini Singh, and Edward J. Boyko 3 Genomics of Diabetic 4 Transgenic and Gene Knockout Analysis of Diabetic Sookja K. Chung and Stephen S. M. Chung 5 Hyperglycemia-Initiated Mechanisms in Diabetic Neuropathy 69 Irina G. Obrosova 6 Effectors Sonic Hedgehog and p38 Mitogen-Activated Sally A. Price, Rebecca C. Burnand, and David R. Tomlinson 7 Neuronal and Schwann Cell Death in Diabetic Neuropathy 113 James W....

Splanchnicmesenteric

Experimental diabetes because of STZ or other models associated with insulin deficiency results in gastric and colonic dilatation and loose stools. Schmidt et al. (20) described distal axonal swellings and dystrophic changes in the ileal mesentery of diabetic rats, containing a variety of normal and unusual subcellular organelles similar to those described in experimental and clinical axonal dystrophies. These alterations, consisting a distinctive distal axonopathy involving terminal axons and...

G

Gabapentin, painful neuropathy management, 359 Gastroesophageal reflux disease (GERD), features in diabetes, 435 Gastrointestinal symptoms constipation, see Constipation diarrhea, see Diarrhea epidemiology in diabetes, 433 esophageal dysfunction, see Esophageal dysfunction fecal incontinence, see Fecal incontinence gastroparesis syndrome, see Gastroparesis syndrome Gastroparesis syndrome clinical findings and evaluation, 437-440 management, 440-442 pathogenesis in diabetes, 436, 437 Genetics,...

Neuropathies Associated With Pain

As stated earlier, a number of the neuropathic syndromes associated with diabetes may be accompanied by painful symptomatology these are summarized in Table 1. Although discussed in detail in Chapter 22, a brief description of those associated with painful symptomatology is provided here (7,8). Those cranial mononeuropathies affecting the nerves supplying the external ocular muscles typically present with sudden onset of diplopia and an ipsilateral headache often described as a dull pain coming...

D

Debridement, foot ulcer management, 487-489 Dementia, see Diabetic encephalopathy Dermagraft, foot ulcer management, 492, 493 Diabetic encephalopathy animal studies behavioral findings, 188 hippocampal synaptic plasticity, 188, 189 neurophysiological changes, 189 overview, 187, 188 pathogenetic mechanisms, 189, 190 structural abnormalities, 189 cognition studies clinical management, 198, 199 type 1 diabetes adults, 191 children, 190, 191 type 2 diabetes, 191-193 dementia studies, 193, 194...

Female Sexual Dysfunction

Female sexual dysfunctions (FSD) include persistent or recurrent disorders of sexual interest desire, disorders of subjective and genital arousal, orgasm disorder, pain and difficulty with attempted or completed intercourse. The scientific knowledge on sexual dysfunction in women with diabetes is rudimentary. Sexual dysfunction was observed in 27 of women with type 1 diabetes. FSD was not related to age, BMI, HbAlc, duration of diabetes, and diabetic complications. However, FSD was related to...

P

P38 mitogen-activated protein kinase, see Mitogen-activated protein kinase P100, diabetes findings, 196, 197 P300, diabetes findings, 197 Painful neuropathy acute painful neuropathy poor glycemic control, 250 rapid glycemic control, 250, 251 animal models, 345, 346 brain changes acute pain responses, 340-342 chronic pain responses, 342, 344, 345 overview, 340 chronic sensorimotor neuropathy, 353, 354 clinical trial design, 356 focal and multifocal neuropathies, 352, 353 general symmetrical...

Nonpharmacological Treatment Of Oh

Nonpharmacological approaches are extremely important (Table 3). Patient Education Patient education is extremely important. The patient should understand in simple terms the maintenance of postural normotension. They need to understand the orthostatic stressors and their mechanisms. Important items of education include the following. 1. Advice on handling early morning and postprandial worsening of OH. 2. Instructions on how to keep a BP log. The patient or caregiver should learn to use an...

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...

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...

Perspective

In this brief review, the applications of TG and gene KO technologies to investigate the pathogenesis of diabetic neuropathy have been discussed. The results of the genetic analyses on the polyol pathway are in complete agreement with findings from ARI studies, thus unambiguously confirming the role of the polyol pathway in the pathogenesis of this disease. These studies also demonstrated that the polyol pathway-induced oxida-tive stress rather than osmotic stress is the cause of the...

Clinical Deficits

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...

End Points For Clinical Trials In Diabetic Neuropathy

Painful symptoms and foot ulceration are the two most important clinical problems related to peripheral somatic diabetic neuropathy. The conduction of clinical trials, which test the efficacy of new therapies for painful neuropathy is straight forward From Contemporary Diabetes Diabetic Neuropathy Clinical Management, Second Edition Edited by A. Veves and R. Malik Humana Press Inc., Totowa, NJ patients with this condition are provided trial medication and the primary end point is the reduction...

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...

Selection Of Biopsy Site And Processing Technique

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...

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 autoimmunity in typical diabetic polyneuropathy might warrant anti-immune approaches. Immune intervention with human intravenous immunoglobulin (IVIg) has become...

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...

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,...

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...

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...

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 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...

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...

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...

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...

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...

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...

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,...

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....

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...

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...

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...

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

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,...

Composite Scores

The reproducibility of the different measures of neuropathy and interobserver agreement varies markedly between tests. This leads to the situation where the analysis for a clinical trial produces some results which are found to be significant whereas others are not, yet they might be assessing the same modality. To overcome this, Dyck and coworkers (43) pioneered composite scores such as the NDS and later the neuropathy impairment score (NIS). This allows an assessment of an alteration in...

Diabetic Foot Ulceration

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...

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...

Pathophysiology Of Microvascular Disease And Endothelial Dysfunction In Diabetes

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...

Sonic Hedgehog And Diabetic Neuropathy

Sonic Diabeaties

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...

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...

Mitogenactivated Protein Kinases

MAPKs are a family of enzymes involved in transducing signals derived from the extracellular environment. There are three main subtypes of MAPKs extracellular regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 MAPKs. All family members are activated by dual phosphorylation of a consensus sequence, Thr-Xxx-Tyr by MAPK kinases. Upstream of these are the MAPK kinase kinases, thereby forming a three kinase cascade. There are fewer different kinases at each subsequent level of the...

Erectile Dysfunction

Penile Neuropathy

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...

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...

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...

Studies In Animals

Outside the field of diabetes research, animal models are widely used to explore the mechanisms of learning and memory. Although many questions remain unanswered, much progress has been made in identifying the cellular and molecular events that underlie the storage of information in specific brain areas. In this respect, the hippocampus, a structure in the medial temporal lobe, has attracted particular attention. Within the hippocampus, activity-dependent plastic changes in the strength of...

Clinical Approach To Complaints Of Cognitive Dysfunction In Diabetic Patients

The data that are reviewed in this chapter clearly show that diabetes is associated with changes in cerebral function and structure. However, it should be noted that the diagnosis diabetic encephalopathy cannot be readily established in individual patients. This is because of the fact that the changes in cognition and in brain structure, as observed on computed tomography or MRI, are not specific to diabetes. There is, for example, considerable overlap with functional and structural changes in...

Studies In Man Therapies

To date the only published studies that have evaluated the effects of different treatment modalities on cognition in type 1 diabetes, are the intensive insulin treatment trials (48,95). In these trials cognition was monitored primarily in order to detect possible unwanted side effects of an increased incidence of hypoglycemic episodes. Neither study detected a deterioration of cognitive function in relation to the occurrence of hypo-glycemic episodes, but they also failed to show an improvement...

Studies In Man Neuropathology And Brain Imaging

Bilateral Basal Ganglia Enhancement Mri

Up till two decades ago, studies on the structural basis of impaired cognition in man largely depended on neuropathology. Much has changed since the introduction of powerful neuroimaging techniques, such as computed tomography, and even more so Magnetic resonance imaging (MRI). Neuroimaging now plays a key role both in daily clinical practice and in cognition and dementia research. In patients suspected of dementia, MR in particular not only serves to exclude (rare) treatable causes of...

Studies In Man Cognition And Dementia

Studies into the effects of diabetes on cognitive functioning in man can be broadly divided in two categories case-control studies, which are mostly cross-sectional, and population-based surveys, which are often longitudinal. The case-control studies usually involved selected populations of patients and matched nondiabetic controls, using performance on a battery of neuropsychological tests as an outcome measure. Population-based surveys mostly involved elderly subjects, and used either...

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)....

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,...

Microangiopathy Diabetes And The Peripheral Nervous System Experimental Studies

Endoneurial Blood Flow

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...

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...