Diabetic Nerve Pain Homeopathic Cure

Dr. Labrum Peripheral Neuropathy Solution

Neuropathy Solution Program was a natural healing developed by Randall Labrum an expert and previous Neuropathy researcher. Diabetes patients ought to care for his or her feet a lot more than they normally do. When your blood sugar levels remains uncontrolled for an prolonged period of time you are able to expand neuropathy. Neuropathy Solution is vastly more efficient than drugs as it targets and corrects the underlying cause of the Neuropathy with a series of techniques that can work in natural harmony with your bodys healing abilities and restorative functions. With six easy steps that include changes in diet, exercise and lifestyle habits, a peripheral neuropathy sufferer can have permanent relief from the many painful, debilitating symptoms in as little as a month, often times even less. More here...

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Diabetic Neuropathy In Western Medicine

Despite his remarkable insight into the nature of diabetes, John Rollo failed to acknowledge a direct link between diabetes and the nervous system. This was not the case with Marchal de Calvi who, in 1864, correctly identified that relationship (12). The works generated at the end of the 19th century had definitively established the concept of peripheral neuropathy as a complication of diabetes. In 1884, Althaus confirmed the findings of de Calvi and emphasized the nocturnal character of pain (13). In that same year, Bouchard pointed to the fact that the knee-jerks are frequently absent in cases of diabetes (14). A few years later, Ross and Bury systematically studied reflexes in 50 patients with diabetes (15). Frederick William Pavy, in his address to the Section of Medicine of the British Medical Association, provided a classical description of neuropathic signs and symptoms associated with diabetes, acknowledging the link between them. His description included heavy legs, numb...

Sonic Hedgehog And 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 velocities in the lower limbs are both increased to values comparable to that of nondiabetic animals (4). In addition, deficits in nerve growth factor and the related peptide substance P, shown in diabetic rats (5), are not present in rats treated with Shh-IgG (4). There is a clear disruption in the gene expression of hedgehog genes in the peripheral nervous system of diabetic animals. The mRNA encoding Dhh is reduced in the sciatic nerve of the diabetic rat (4). In addition, shh was downregulated...

Oxidative And Nitrosative Induced Cell Death In Diabetic Neuropathy

One potential stimulus for O2 generation is NO (60). NO by interaction with the electron transport chain functions not only acts as a physiological regulator of cell respiration, but also augments the generation of ROS by Mt, and can trigger PCD (61). Evidence of increased production of reactive nitrogen species (NO and ONOO) coupled with evidence of PCD implicate nitrosative injury in models of diabetic neuropathy (62,63). NO is formed by activation of NO synthase (NOS), which analyzes the oxidation of L-arginine to NO and citrulline (for review see ref. 64). Neuronal NOS is the primary constitutively active isoform in neurons. NO is relatively unstable in vivo, however, it can bind thiol-containing proteins, thereby substantially increasing its halflife. This process, called S-nitrosylation results in directed and rapid activation or deac-tivation of proteins and affects the signaling of specific proteins (64-67). Activation of neuronal NOS, endothelial NOS, or the inducible form of...

Intracranial hemorrhage or vascular occlusion 10 Mononeuropathy singlemultiplex

Disturbed function of one or more peripheral nerve(s) resulting in weakness paralysis or sensory dysfunction because of either conduction block in motor nerve fibers or axonal loss. a. Clinical demonstration of motor sensory disturbances in the distribution of a peripheral nerve and or

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 associated with neuropathy are also markers of insulin resistance, which is in turn associated with endothelial dysfunction. The latter, as previously discussed, causes tissue functional ischemia and is believed to be a pivotal factor in the development of diabetic neuropathy. It is clear that impaired blood flow and endoneurial hypoxia are the major pathogenic factors in the development of diabetic peripheral neuropathy. Thus, arterial obstructive lesions, even occurring at the large vessels of the...

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 of the symptoms, which is expected to occur during a reasonable period after the treatment has been initiated. In contrast, foot ulcers develop long after the initiation of events which lead to nerve damage and, by this time, the possibility of restoring the nerve lesions, or halting their progression, is close to nonexisting. Therefore, if a study was to be conducted having as primary end point the prevention of foot ulceration it should involve patients who have diabetic neuropathy in the...

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 treatments for pain must rely upon the patients' response to questions, questionnaires, or other measures. This principle has not been followed in all trials for example, it is inadmissible to rely on the physician's overall impression of the patient's response as was the case in one trial (12). In recent years, a number of valid measures for the assessment of chronic neuropathic pain and for the evaluation of treatment responses have been developed and tested. One or more of the following methods are...

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 measuring QoL. Until recently, the studies which reported that neuropathy can have a negative impact on the functioning and QoL relied upon generic instruments, which do not describe the condition-specific features of neuropathy. Thus, Vileikyte et al. (24) developed the first neuropathy-specific QoL instrument, NeuroQoL, which investigates the impact of symptoms and or foot ulceration as a consequence of neuropathy on QoL. The results of this study demonstrated that patients experiencing...

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 intravenous immunoglobulins (42), but it should be kept in mind that the overall spontaneous prognosis of focal diabetic neuropathies is good.

Overview Of The Peripheral Nervous System

The peripheral nervous system arises from specialized cells (neural crest cells) located along the lateral edges of the neural plate (see Fig. 1). These cells bud off and become separated from the neural tube as it forms. Some groups of neural crest cells migrate to form a linear array of dorsal root ganglia located adjacent to the lateral borders of the spinal cord. These cells function as sensory

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 epidemiology, diabetes, and neuropathy from 1966 to February 2005 review of bibliographies of the articles obtained from the Medline search for relevant citations, and review of the authors' files. Clinic-based cross-sectional or case-control studies have not been considered except in the case of rare conditions for which no other data exists, because of the potential problem of selection bias associated with these study designs (1). All prospective studies, and some randomized controlled trials,...

Microangiopathy Diabetes And The Peripheral Nervous System Experimental Studies

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 the changes of diabetic neuropathy. Although this body of work has undoubtedly provided evidence of a linkage, cause and effect has not been proven. A number of the reports have arisen from relatively few experimental laboratories (33,34,64-97). Similarly, the spectrum of agents reported to correct blood flow and conduction slowing has been very wide. As such, this range of apparently beneficial interventions raises the strong possibility that they exert parallel benefits on separate, but...

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, and some stabbing discomfort with variable allodynia, and most have normal motor function. There is a subset of patients with completely normal motor function, intact tendon reflexes, and nerve conduction studies that are normal or near-normal. For this pattern of neuropathy, the underlying neuropathy has been assumed to be a length-dependent distal small fiber neuropathy demonstrable on skin biopsy (86). Autonomic fibers are presumed to be involved as well because these patients will usually have...

Treatment Of Painful Diabetic Neuropathy

Glycemic Control and Painful Diabetic Neuropathy A number of studies have confirmed the major contribution of prolonged hyperglycemia in the pathogenesis of neuropathy and neuropathic pain (30-33). More recent studies in patients with idiopathic painful neuropathies further support the relationship between hyperglycemia and painful neuropathy. In the study of Singleton et al. (34), impaired glucose tolerance was more common in patients with idiopathic painful neuropathy than the general population. Thus, achieving near normoglycemia should be the primary aim in both the prevention of and the first step in the management of generalized peripheral neuropathy. A number of small open-label uncontrolled studies have suggested that achieving stable near-normoglycemia is helpful in the management of painful neuropathic symptoms. In one such study (35), patients with painful neuropathy were treated with continuous subcutaneous insulin infusion for a period of 4 months. As well as resulting in...

Diabetic Neuropathy

About half of all people with diabetes experience some degree of diabetic neuropathy, which can present either as polyneuropathy or mononeuropathy (109). Diabetic neuropathy can also affect the central and the autonomic nervous systems. Level of hyperglycemia seems to determine the onset and progression of diabetic neuropathy (110,111). Diabetic rats show reduction in sensory motor conduction velocities and nerve action potentials and reduction in peripheral nerve blood flow and all these abnormalities can be prevented by pretreatment with anti-AGE agents such as aminoguanidine (114,115). Pentosidine content was increased in cytoskeletal proteins of the sciatic nerve of streptozotocin induced diabetic rats and decreased after islet transplantation (111). Pentosidine content was found elevated in cytoskeletal and myelin protein extracts of sural nerve from human subjects (116). The sural and peroneal nerves of human diabetic subjects contain AGEs in the perineurium, endothelial cells,...

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 , respectively (40). Ulnar and femoral cutaneous entrapment was found in 2 of type 1 diabetes and 1 of type 2 diabetes subjects. Cranial mononeuropathy and trun-cal radiculopathy were not observed in the Rochester population, whereas proximal asymmetric polyneuropathy was identified in 1 of type 1 diabetes and type 2 diabetes subjects (40). No incidence data were available for any of these types of neuropathy. In a cross-sectional, hospital-based study, O'Hare et al. (41) studied the presence of...

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 subjects with type 2 diabetes, after 6 years follow-up, biosthesiometer readings in both toes were abnormal in 19 of intensively treated subjects and in 21 of conventionally treated controls (19). These two studies cannot be directly compared because the methods of defining neuropathy, and the time intervals at which results were described, are both different. However, the frequency with which the control subjects in the DCCT trial developed abnormal nerve conduction is striking. Broadly...

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 easily translate into clinical practice. Important potential confounding variables must be considered in future studies, including alcohol consumption in particular, height, and possibly nutritional factors as well. Further investigation of the association between hyperlipidemia and risk of neuropathy is warranted to examine the possibility that this complication may have, in part, a macrovascular etiology. Prospective studies of large cohorts of diabetic subjects would likely yield the best...

Nonenzymatic Glycation

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, attenuated MNCV, and sensory NCV (SNCV) deficits in diabetic rats (39,40). However, besides inhibition of AGE formation, aminoguanidine is known to inhibit the activity of other enzymes including the inducible-, neuronal-, and endothelial-nitric oxide synthases, and the semicarbazide-sensitive amine oxidase (41). It is likely that there might be still other enzymes that are affected by this drug. Therefore, it is not clear if the beneficial effect of this drug on diabetic neuropathy is the consequence of inhibition of AGE formation. One of the mechanisms by which AGE exerts its toxic effects is its interaction with its receptor for advanced glycation end products (RAGE) (42,43). This leads to the activation of a cascade of cytotoxic pathways, including...

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 diabetic neuropathy has been extensively reviewed (63-65). A number of new studies in animal models of diabetes and human subjects support the role of this mechanism. Using the state-of-the art technique, i.e., liquid chromatography with tandem mass spectrometry (MS) detection, Karachalias et al. (66) produced evidence of accumulation of fructosyl-lysine and AGE in peripheral nerve of STZ-diabetic rats. In particular, sciatic nerve concentrations of NMcarboxymethyl -lysine and - carboxyethyl -lysine...

Role For Pkc Activation

The experimental evidence obtained with various PKC inhibitors as well as the dia-cylglycerol complexing agent cremophor by several groups (81,86-88) suggests the detrimental role of PKC activation in vasa nervorum. The PKC inhibitors, WAY151003, chelerythrine, and LY333531 as well as cremophor prevented or reversed NBF and conduction deficits (81,86,87), and the PKC inhibitor Ws-indolylmaleimide-1HCl corrected acetylcholine-mediated vascular relaxation in epineurial arterioles in the STZ-diabetic rat model (88). The role for neural PKC in the pathogenesis of PDN remains unclear. However, recent findings suggest that neuronal PKC might be related to diabetes-associated changes in expression, phosphorylation, and function of the vanilloid receptor 1, known to play an important role in diabetic neuropathic pain (89). The novel PKC-P isoform selective inhibitor JTT-010 was found to ameliorate nerve conduction deficits, hyperalgesia (formalin test in its first phase), and hypoalgesia...

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 peripheral nerve. In addition, new markers of ROS-induced injury have been identified in peripheral nerve, vasa nervorum, and DRG in experimental PDN. Those include decreased catalase and total quinone reductase activities, depletion of ascorbate and taurine, and increase in dehydroascorbate ascorbate ratio in peripheral nerve (91,92), increased production of superoxide in vasa nervorum (23), and accumulation of 8-hydroxy-2'-deoxyguanosine in DRG of STZ-diabetic rats (19). Diabetes-induced...

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

Recent studies of the author's group (8,26,27) revealed that PARP activation is an early and fundamental mechanism of PDN. It is clearly manifest in peripheral nerve, vasa nervorum, and DRG neurons of STZ-diabetic rats (8,26,27,93) as well as peripheral nerves of STZ-diabetic (94) and ob ob mice (58). Using endothelial and Schwann cell markers and double immunostaining (8), the author's group localized PARP activation in endothelial and Schwann cells of diabetic rat nerve. The group was first to develop the Western blot analysis of poly(ADP)-ribosylated proteins in rat sciatic nerve (27) using this approach, it was found that poly(ADP)-ribosylated protein abundance increased by 74 in rats with 4-weeks duration of STZ-diabetes in comparison with nondiabetic controls. Furthermore, accumulation of poly(ADP)-ribosylated proteins was found to develop very early, i.e., within about 12-24 hours of exposure of cultured human endothelial and Schwann cells to high glucose (27). PARP-1 protein...

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 complex called the death-inducing signaling complex. Formation of the death-inducing signaling complex activates the initiator caspase, caspase-8, which then cleaves and activates the effector caspase-3, resulting in PCD (12-14). Although the extrinsic pathway is less well-characterized in diabetic complications, there is evidence of FasL activation in association with diabetic neuropathy. Circulating soluble Fas and soluble FasL, two transmembrane glycoproteins involved in apoptosis are...

Underlying Metabolic Abnormalities In Type 1 And Type 2

These regulatory functions by insulin C-peptide are reflected in a more severe suppression of IGF's IGF-IR, insulin receptor and NGF and TrkA receptor expression in dorsal root ganglia and peripheral nerve in the type 1 BB Wor-rat as in comparison with the type 2 counterpart (45,46). Such differences therefore will have consequences such as regenerative capacities, survival of neuropeptide specific neuronal populations, and maintenance of axonal integrity (41,45,46).

Structural Abnormalities In Type 1 And Type 2

The molecular compositions of the node of Ranvier and the paranodal apparatus are complex (Fig. 5) (88,89). Voltage-gated Na+ channels are concentrated to the nodal axolemma. They consist of the pore-forming Na+ channel a-subunit and two auxiliary Na+ channel subunits P1 and P2, which act as adhesive anchors (90) and interact with axonal ankyrinG (91). The P-subunits also interact with neurofascin, Nr-CAM, N-cadherin and L1 (89,92) mediating contacts with Schwann cell microvilli. Post-translational modification of ankyrinG by O-linked N-acetyl-glycosamine, inhibits phosphorylation of serin residues and prevents interaction with the P-subunits, and its interaction with receptor protein tyrosin phosphatase (RPTP)-P, which is mediated by tyrosine phosphorylation sites (61,93,94). It should be mentioned that the high affinity insulin receptor in peripheral nerve is concentrated to the nodal axolemma and colocalizes with axoglial junctions at the paranode (Fig. 5) (95). Therefore, the...

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 such as inexperience with a label or contaminating nutritive flow with arteriovenous shunt flow. This reduction is because of impairment of nitric oxide synthase activity (2,3) and is initially reversible. To address the issue of whether the impaired perfusion is pathophysiologically important, Cameron et al. (4) regressed nerve blood flow against nerve conduction velocity. There is a close relationship between nerve blood flow and nerve conduction slowing (Fig. 1). This relationship highlights the...

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 and their ensheathing Schwann cells. The nerve fibers tend to run parallel with capillaries, but have no close association with either the capillaries or the secretory epithelium. Capillaries provide an abundant blood supply to the sweat gland and are fenestrated. The relationships between cellular elements of the sweat gland provide no direct

Spinal Neurochemistry In Diabetes

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 spinal sensory pathways is responsible for diabetic neuropathic pain and is secondary to enhanced excitatory input from peripheral nerve primary afferent fibers. This is difficult to verify in clinical studies, whereas evidence of spontaneous or exaggerated evoked activity of primary afferents in animal models of diabetes has been reported in some studies (56-59) but also discounted in others (60,61). Of course, electrical activity of sensory fibers is only one component of any altered input to the spinal cord and other factors, such as the amount of available neurotransmitters and patency of vesicular release mechanisms, must also be considered. To date, few...

Blood Flow Of Nerve Trunks And Ganglia

Spinal dorsal root ganglia are supplied from segmental radicular arteries and anastamoses with branches of spinal arteries (7). Unlike the peripheral nerve trunk, they do not have a prominent extracapsular plexus. Neuron perikarya that entrain higher metabolic requirements are most often located in the subcapsular space, whereas axons eventually entering roots are more frequently found in the core of the ganglia. Given this structure, microanatomic susceptibility of the ganglia to ischemia is probably even less predictable than that of nerve trunks. Peripheral nerve trunks are supplied by blood vessels from two distinct compartments the epineurial vascular plexus and the intrinsic endoneurial blood supply. Although, extrinsic epineurial blood flow is ultimately responsible for downstream blood flow in the endoneurial compartment, each compartment has distinct physiological and morphological characteristics. The epineurial plexus, as discussed, is well-perfused by arterioles, has...

Symmetrical Neuropathies

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, with a similar progression proximally starting in the fingers. Although the nerve damage can extend over the entire body including the head and face, this is exceptional. Subclinical neuropathy detectable by autonomic function tests is usually present. However, clinical autonomic neuropathy is less common. Autonomic neuropathy is considered in more detail in Chapter 24. As the disease advances, overt motor manifestations, such as wasting of the small muscles of the hands and limb weakness become apparent. However, subclinical...

Acute Painful Neuropathies

On sural nerve biopsy, typical morphometric changes of chronic distal symmetrical neuropathy but with active regeneration, were observed (49). In contrast, degeneration of both myelinated and unmyelinated fibres was found in acute painful neuropathy of poor glycemic control (44). A recent study looking into the epineurial vessels of sural nerves in patients with acute painful neuropathy of rapid glycemic control demonstrated marked arterio venous abnormality including the presence of proliferating new vessels, similar to those found in the retina (48). The study suggested that the presence of this fine network of epineural vessels may lead to a steal effect rendering the endoneurium ischaemic, and the authors also suggested that this process may be important in the genesis of neuropathic pain (48). These findings were also supported by studies in experimental diabetes, which demonstrated that insulin administration led to acute endoneurial hypoxia, by increasing nerve arterio-venous...

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). Asymmetrical neuropathies are more common in men and tend to predominantly affect older patients (52). A careful history is therefore mandatory in order to identify any associated symptoms that might point to another cause for the neuropathy. A vascular etiology has been suggested by virtue of the rapid onset of symptoms and the focal nature of the neuropathic syndromes (53). The cause of diabetic proximal motor neuropathy is not known. It tends to occur within the background of diabetic...

Pathophysiology Of Microvascular Disease And Endothelial Dysfunction In Diabetes

Microvascular Dysfunction and Diabetic Neuropathy Microvascular reactivity is further reduced at the foot level in presence of peripheral diabetic neuropathy. Endothelial nitric oxide synthase (eNOS) is a key regulator of vascular nitric oxide production. Immunostaining of foot skin biopsies in our unit, with antiserum to human eNOS glucose transporter I, which is a functional marker of the endothelium and von Willebrand factor, an anatomical marker, showed no difference among patients with diabetes with or without peripheral neuropathy in the staining of glucose transporter I and von Willebrand factor, whereas the staining for the eNOS was reduced in neuropathic patients (Fig. 2) (18). Another study documented increased levels of iNOS and reduced eNOS levels in skin from the foot of patients with diabetes with severe neuropathy and foot ulceration (19). It has also been suggested that polymorphism of the eNOS gene is implicated in cardiovascular and renal diseases, thus indicating...

Correlation Between Epidermal Nerve And Sural Nerve

Measurement of cutaneous innervation has proven to be particularly useful in the study of diabetic neuropathy. Abnormalities in epidermal innervation have been demonstrated to be more sensitive for the diagnosis of diabetic neuropathy than clinical or electrophysiological methods. Several investigators have demonstrated that dermal PGP immunoreac-tivity was reduced in subjects with diabetes testing normal on clinical examination, electrophysiology, and quantitative sensory testing (QST) when compared with healthy control subjects (22). This likely reflects the observation that small unmyelinated nerve fibers are vulnerable early in diabetes (23). Evaluation of epidermal nerve fibers (ENFs) appear to be even more sensitive, perhaps because of their further distance from the cell body, absence of a Schwann cell or collagen covering sheath, and the avascular nature of the epidermis that increase their susceptibility to disease. Kennedy demonstrated that subjects with diabetes had reduced...

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 were noticed in this trial (Table 1).

Therapies Targeted To Metabolic Pathways

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 and disruption of the microvascu-lature in the peripheral nervous system (Fig. 2). It has been shown that there is an increased presence of markers of oxidative stress, such as superoxide and peroxynitrite ions, and that antioxidant moieties were reduced in patients with diabetic peripheral a-lipoic acid is the best studied antioxidant therapy used in diabetic neuropathy. Lipoic acid (1,2-dithiolane-3-pentanoic acid), a derivative of octanoic acid, is present in food and is also synthesized by the liver. It is a natural cofactor in the pyruvate dehy-drogenase complex where it binds...

Inhibitors Of Glycation

Animal studies using aminoguanidine, an inhibitor of the formation of AGEs, showed improvement in nerve conduction velocity in rats with STZ-induced diabetic neuropathy. However, controlled clinical trials to determine its efficacy in humans have been discontinued because of toxicity (19,20). However, there are compounds related to aminoguanidine that reduced AGE formation and hold promise for this approach, although these have not been systematically studied in humans (21-24).

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 appropriate in some patients with forms of peripheral diabetic neuropathy that are associated with signs of antineuronal autoimmunity (94,95). Chronic inflammatory demyelinating polyneuropathy associated with diabetes is particularly responsive to IVIg infusion. Treatment with immunoglobulin is well tolerated and is considered safe, especially with respect to viral transmission (96). The major toxicity of IVIg has been an anaphylactic reaction, but the frequency of these reactions is now low and...

Therapies For Nerve Regeneration

Neurons affected in diabetic neuropathy are developmentally dependent on NGF. Therefore, a decline in NGF synthesis in patients with diabetes plays a role in the Neurotrophic proteins are reduced in patients with diabetes. NGF protein levels in the serum of patients with diabetes are suppressed (108). Additionally, diabetes might result in decreased serum IGF and increased IGF-I binding protein-I (109) thereby inhibiting the protein's downstream effects. Despite increasing evidence that growth factors are suppressed in patients with diabetes, there is no direct link between neurotrophic factors and the pathogenesis of diabetic neuropathy (99) and preliminary studies of both NGF and NT3 treatment have met with limited success. There is now considerable evidence in animal models of diabetes that decreased expression of NGF and its high-affinity receptor, trk A, reduces retrograde axonal transport of NGF and diminishes support of small unmyelinated neurons and their neuropeptides, such...

Clinical Trial Design For Painful Neuropathy Trials

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 during a period of months (9). In contrast, chronic painful neuropathy is of insidious onset and although the symptoms are similar in character to those of acute neuropathy, on examination there is usually a peripheral sensory loss to multiple modalities and absent ankle reflexes. The natural history of this condition is that whereas the symptoms may wax and wane and persist for several years, the disappearance of symptoms is not necessarily a sign of improvement but might represent progression to the insensitive foot (25). It is clearly important in view of the difference in natural history, that trials of any potential new treatments should only include...

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 the cavernous sinus, of the posterior communicating artery, or a fusiform aneurysm of the top of the basilar artery. Imaging will also permit to exclude tumors occurring at the base of the brain or in the basal skull. In patients with progressive involvement of several cranial nerves without imaging abnormalities, examination of the CSF might detect malignant cells characteristic of a carcinomatous meningitis. In patients with diabetes who develop a focal or multifocal neuropathy of the limbs,...

Regulation Of Blood Pressure

Bed is markedly responsive to both arterial and venous baroreflexes. Venoconstriction is mediated by a-adrenergic receptors (9). The nerve supply to the mesenteric bed is mostly from preganglionic axon in the greater splanchnic nerve, with cell bodies in the intermedi-olateral column (mainly T4-T9) that synapse in the celiac ganglion from where postganglionic adrenergic fibers supply effector cells. Abnormalities in the splanchnic autonomic outflow have been found in human diabetic neuropathy, indicating that preganglionic fibers can be affected (10).

Diabetic Foot Ulceration

It is important to note that most of these risk factors do not act independently to produce foot ulceration. Instead, it is usually a combination of these risk factors that triggers a pathway leading to ulceration. Such risk factors can consist of a number of component causes, such as peripheral neuropathy, foot trauma, foot deformity, lower limb ischemia, foot edema, and callus formation. However, some risk factors seem to be more important in causing ulcerations. A critical triad of neuropathy, minor foot trauma, and foot deformity was found in more than 63 of foot ulcers in one study (27). As shown in Fig. 1, in the vast majority of diabetic foot ulceration, the first major component is the development of sensory neuropathy that causes pain insensitivity (11). The next component is the development of trauma, usually related to the high foot pressures that develop under the foot during walking. The trauma caused by the elevated foot pressures seen during normal walking are often the...

Charcot Neuroarthropathy

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 Charcot neuroarthropathy. Fig. 9. (A) Midfoot Charcot neuroarthropathy in a patient with diabetes with severe peripheral neuropathy. Severe foot deformity has resulted to an area where high pressures have been applied during walking leading to extensive ulceration. (B) X-ray from the same patient shows extensive destruction of the midfoot joints. Fig. 9. (A) Midfoot Charcot neuroarthropathy in a patient with diabetes with severe peripheral neuropathy. Severe foot deformity has resulted to an area...

Therapies For Microvascular Insufficiency

Multiple studies using a specific PKC-P inhibitor, ruboxistaurin mesylate (LY333531), have shown improvements in diabetic neuropathy. One study in obese rats observed that ruboxistaurin increased resting nitric oxide concentration, and reduced nitric oxide by 15 , indicating that this action is a PKC-P dependent phenomenon (33). Ruboxistaurin has been shown to improve nitric oxide-dependent vascular and autonomic nerve dysfunction in diabetic mice (46). In addition to improving nitric oxide levels, ruboxis-taurin improves nerve function and blood flow. Ruboxistaurin corrected the diabetic reduction in sciatic endoneurial blood flow, sciatic motor, and saphenous sensory nerve conduction velocity in diabetic rats (40,43). In another study, the investigators measured sciatic nerve, superior cervical ganglion blood flow, and nerve conduction velocity in STZ treated rats. After 8 weeks, the authors observed that diabetes reduced sciatic nerve and superior cervical ganglion blood flow by 50...

Gastroduodenal Dysfunction The Gastroparesis Syndrome

Gastroparesis affects both type 1 and type 2 forms of diabetes (13). Diabetic neuropathy is present in about two-thirds of gastroparetic patients with type 1 and about one-fifth with type 2 diabetes (2). One study (33) examined the relationship between gastric emptying parameters, gastric symptoms, and cardiovascular autonomic function. In addition, they found no significant relationship between the prevalence of GI symptoms and abnormalities in gastric emptying. Neither there was any significant relationship between delayed gastric emptying and cardiovascular autonomic neuropathy in their group of patients (33). When symptomatic, gastroparesis manifests by episodes of nausea and vomiting (fasting as well as postprandial) that are often, but not invariably associated with upper abdominal pain. Dyspeptic symptoms such as early satiety, frequent belching as well as bloating might be present. On abdominal examination, a gastric splash might be detected, but it is rare. The episodes of...

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 lower extremity amputation in the population with diabetes is 15 times that seen in the population without diabetes and within 4 years of the first amputation about 50 of contralateral limbs are lost (46,47). Life expectancy is also consistently reduced, as a result (48). The clinical presentation of PVD in diabetes is also different because of the coexistence of peripheral neuropathy. In fact, while in patients without diabetes intermittent claudication defined as pain, cramping or aching in...

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 recombinant human nerve growth factor (NFG) in HIV-sensory neuropathy, 62 of 270 patients who participated in the trial were included in a substudy examining the density of intraepidermal nerve fibers. Fiber density was inversely correlated with neuropathic pain as measured both by patient and physician global pain assessments (10). The intrasubject reproducibility of the technique, as assessed from correlation between baseline and the week 18 densities was 81 in the distal part of the leg, and 77 in the...

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 clearly separates them into three distinct groups (Table 2). Based on the various distinct clinical presentations to the physician, Ward recommended a classification of diabetic polyneuropathy depicted in Table 3 (10). This practical approach to the classification of diabetic neuropathies provides the clinician to have workable, crude definitions for the various neuropathic syndromes, and also assists in the management of the patient. Classification of Diabetic Neuropathy Large-fiber type of...

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 cardiovagal function became more pronounced and was associated with increased resting heart rate. Similar observations were reported in spontaneous diabetes in the WBN Kob rat (9). Florid hyperglycemia was present by 8-9 months, at which time there was a loss of the circadian rhythm of the heart rate and BP with a loss of the nocturnal fall in BP. Sympathetic failure is typically preceded by evidence of sympathetic overactivity, and much of the resting tachycardia is sympathetic in origin....

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 receptor antagonist L158809 (7). In author's study (20), prazosin prevented diabetes-induced neurovascular dysfunction and MNCV deficit, without counteracting accumulation of sorbitol pathway intermediates, depletion of myo-inositol and taurine, downregulation of Na, K-ATPase activity, and enhanced lipid peroxidation in the peripheral nerve. Therefore, none of these neurochemical changes appears to be of critical importance for the development of nerve conduction slowing in, at least, short-term...

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 not disputed and the pathology has been well documented. The following section will first consider morphological evidence from autopsy material for diabetes-induced injury to the spinal cord, associated ganglia and roots, and then available evidence from studies using experimental models of diabetes. Similar to peripheral neuropathy, radiculopathy is a frequently described manifestation of diabetes mellitus and is well documented in the literature. Williamson described degenerated nerve...

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 triggered a wide interest and more systematic approach to research of diabetic complications, leading to S. Fagerberger's conclusion that many of them share the underlying microvascular pathology. The history of diabetic complications, including neuropathies, cannot be separated from the one of diabetes itself. Ancient texts describing what is believed to be diabetes mellitus represent clinical records of polyuric states associated with increased thirst, muscle wasting, and premature death. In...

The Ancient Period

From Contemporary Diabetes Diabetic Neuropathy Clinical Management, Second Edition Edited by A. Veves and R. Malik Humana Press Inc., Totowa, NJ Susruta may deserve credit for what seems to be the very first record of symptoms attributable to diabetic neuropathy Their premonitory symptoms are feeling of burning in the palms and soles, body (skin) becoming unctuous and slimy and feel heavy, urine is sweet, bad in smell, and white in color, and profound thirst Complications (upadrava) include diarrhea, constipation, and fainting (6). Susruta also made a very important observation that the disease affects two types of people the older, heavier ones and the thin who did not survive long. All other known early records that most likely represent a description of some form of diabetic neuropathy come from the Orient. Persian philosopher and physician Ibn Sina, known as Avicenna (980-1037 ad) in the West, described diabetes in his famous El-Kanun. He observed gangrene and the collapse of...

Candidate Genes

Genetic models can also be used to identify the susceptibility risk factor. Rogus et al. (28) have studied the genetic association between diabetic complications and diabetes duration by using a genetic model. Genetic models might be used to study a single major genetic effect whereby, carriage noncarriage of a risk allele essentially indicates who will become affected, and a subtle minor genetic effect that simply shortens or lengthens the duration at which onset occurs. On a broader level, these results highlight the need to be cognizant of diabetes duration before onset of proteinuria or other late diabetic complications in family-based trio studies. To date, there have been no family studies looking at diabetic neuropathy. The understanding of the mechanisms of brain and nervous system function has been greatly aided by the discovery of genes responsible for specific neurological disorders. These results will hopefully allow the genetic factors responsible for diabetic neuropathy...

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 diabetic neuropathy, retinopathy, and nephropathy. AR also reduces galactose to form galactitol. Because a high galactose diet also produces tissue lesions similar to diabetic lesions, galactosemia has been used as an experimental surrogate for diabetes. It has also been suggested that conversion of sorbitol to fructose by SDH causes reduction of NAD+ NADH ratio, creating a pseudohypoxic state that might contribute to the deleterious effects of hyperglycemia (10). As galactitol is not metabolized by...

Parp Activation

The PARP-1 gene KO mice were used to determine if PARP contributes to diabetic neuropathy. These mice showed no obvious abnormality. Under normal rearing condition, the MNCV of their sciatic nerve, the SNCV of their digital nerve, and the morphology of their sciatic nerve all appeared normal (56). When the WT mice were induced to become diabetic by streptozotocin, their MNCV and SNCV decreased significantly. In the sciatic nerve of the diabetic WT mice there was significant increase in immunostaining of PAR, the product of PARP activity, indicating that hyperglycemia activates PARP. The PARP-1 null mice on the other hand, showed no reduction in MNCV and SNCV when induced to become diabetic. The blood glucose level in the diabetic PARP null mice was not different from that of the diabetic WT mice, indicating that PARP did not affect diabetes, but plays an important role in the diabetes-induced functional impairment in the peripheral nerves. When fed a high galactose diet, which...

Neurofilament

The fact that the NF-deficient mice were more susceptible to diabetes-induced lesions indicates that NF has protective effect on diabetic neuropathy. However, it is not clear whether this finding is relevant to the pathogenesis of the disease in WT animals where slowing of NCV is associated with aberrant phosphorylation of NF rather than the lack of it (60). The decrease in NCV is one of the earliest sign of hyperglycemia-induced lesion, whereas loss of NF occurs only after prolonged hyperglycemia (63). It is possible that loss of NF is the consequence of neuropathy rather than a contributing factor of the disease. The significant NCV slowing and structural abnormalities in the peripheral nerve of the NF-deficient mice before induction of diabetes make interpretation of the results difficult. At this point, it is not clear how the aberrant phosphoryla-tion of NF might contribute to the pathogenesis of diabetic neuropathy.

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 diabetes-induced toxicity, and that the mechanism involves the activation of PARP. The experiments with RAGE null mice demonstrated that interaction between plasma AGE and RAGE is the main source of toxicity induced by nonenzymatic glycation. The contribution by intracellular AGE and AGE attached to extracellular matrix to diabetic neuropathy remains unclear. The finding that the development of diabetic neuropathy is accelerated in NF-deficient mice is difficult to interpret because these mice already...

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 increased flux through SDH leads to so called pseudohypoxia, i.e., an increased free cytosolic NADH NAD+ (12) ratio, whereas others (36) did not find a relation between cytosolic or mitochondrial NAD+ NADH redox state and SDH activity in the peripheral nerve. Two groups obtained the results indicating that increased AR, but not SDH, activity contributes to PDN (37,38). Furthermore, SDH inhibition appeared detrimental rather than beneficial, for autonomic neuropathy (39). The role for AR in PDN...

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 severe chromatin clumping, and perikaryeal vacuolation consistent with Mt ballooning and disruption of the internal Mt cristae structure. Similar observations have been made in vitro using the chromatin stain bisbenzamide. Under high glucose conditions, SC nuclei break apart into brightly staining apoptotic clusters indicative of chromatin condensation and nuclear fragmentation, changes that are confirmed with TUNEL and propidium iodide staining. Furthermore, high glucose conditions promote...

Growth Factors

VEGF was originally discovered as an endothelial-specific growth factor with a predominant role in angiogenesis and retinopathy (73). However, recent observations indicate that VEGF also has direct effects on neurons and glial cells stimulating their growth, survival, and axonal outgrowth (74). Thus with its potential for a dual impact on both the vasculature and neurones it could represent an important therapeutic intervention in diabetic neuropathy (75). A transient increase in the transcriptional regulator hypoxia-inducible factor-1a and a number of its target genes including VEGF and erythropoietin has been demonstrated recently in diabetic rats (76). Similarly in the STZ-diabetic rat intense VEGF staining has been shown in cell bodies and nerve fibers compared with no or very little VEGF in controls and animals treated with insulin orNGF (77). After 4-week intramuscular gene transfer of plasmid DNA encoding VEGF-1 2 nerve vascularity, blood flow, and both large and small fiber...

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. Diabetologia 1993 36 150-154. 4. Maser RE, Steenkiste AR, Dorman JS, et al. Epidemiological correlates of diabetic neuropathy. Report from Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes 1989 38 1456-1461. 5. Ziegler D. Diagnosis, staging and epidemiology of diabetic peripheral neuropathy. Diab Nutr Metab 1994 7 342-348. 6. Tesfaye S, Chaturvedi N, Eaton SEM, Witte D, Ward JD, Fuller J. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005 352 341-350. 8. Tesfaye S....

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 is normally absent. Negative sensory symptoms include numbness, wooden, rubber, or dead feet feeling and commonly used descriptors are a wrapped feeling, retained sock feeling, cotton wool under soles, and so on. Hyperalgesia and allodynia are also prominent elements of the neuropathic sensory symptom complex and are defined as hypersensitivity to a normally mild painful stimulus and painful sensation evoked by a normally nonpainful stimulus, respectively. In the vast majority of patients both...

Clinical Deficits

0-4 produces an accurate and reproducible measure of the severity of diabetic neuropathy (16). However, because it should be performed by well-trained neurologist who can accurately evaluate muscle strength and grade the severity of sensory deficits, it renders it a useful research tool but limits its role in daily clinical practice. A modified NDS first described by Young et al. (17) can be performed by a nonspecialist and provides a sum of the sensory and reflex deficits totalling 28. The sensory score is derived from an evaluation of pain (pin prick), touch (cotton wool), cold (tuning fork immersed in icy water), and vibration (128 Hz tuning fork), graded according to the anatomical level at which sensation is impaired (no abnormality 0 , base of toes 1 , midfoot 2 , ankle 3 , mid-leg 4 , knee 5 ). The average of both feet for each modality is calculated and the sum of all four deficits represents the sensory score. The reflex score is derived from the knee and ankle reflexes...

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 recently shown to be efficacious in the management of neuropathic pain (116). Unfortunately, it was first examined only in normal animals and had no hypo-glycemic properties. It has now undergone extensive testing for epilepsy, migraine, involuntary movements, central nervous system injury, and neuropathic pain. The first two studies used a titration to 400 mg day, which was associated with fairly severe central nervous system side effects, which were prohibitive. The studies failed to establish...

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 cerebral correlates of central processes related to pain and central sensitization has only been possible during last decade and a half with introduction of neuroimaging. Noninvasive brain imaging technologies provide the opportunity to directly study human clinical conditions. Initially, blood flow based positron emission tomography (PET) scan was utilized (9), but advantages of functional magnetic resonance imaging (fMRI), such as improved temporal and spatial resolution have made it a method...

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 autonomic function data should be standardized by the development of reference ranges in the local population as well as by reporting absolute data (8). As described later, indirect assessment of CAN utilizing more indirect reflex tests tend to yield lower overall estimates of CAN prevalence compared with newer direct scintigraphic methodology.

Management

Increased oxidative stress has emerged as a leading candidate in the pathogenesis of experimental diabetic neuropathy, with a direct relationship between measures of oxida-tive stress and the development of nerve blood flow and nerve conduction deficits (146-148). In diabetic rodents, measures of oxidative stress, including increased nerve conjugated dienes (148) and reduced levels of nerve superoxide dismutase (146,149), glutathione peroxidase (150), glutathione (151), and norepinephine (152) are closely associated with the development of neuropathy. In concert, oxidative stress has also been implicated in the development of cardiomyopathy (120,153) and a contributing factor to endothelial dysfunction (154,155) and changes in acute phase reactants (156). Increases in reactive oxygen species can stimulate apoptosis in cardiac myocytes (157,158) potentially resulting in myocardial dysfunction (159). In the heart, chronic oxidative stress might also impair neurotrophism by depleting...

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 any symptoms of autonomic failure. The prevalence of symptomatic OH is less than 1 in population based studies (19), but if asymptomatic OH is considered the prevalence, might be about 10 (ongoing Rochester diabetic study of PJ Dyck). The mechanism of diabetic OH is multiplex. There is denervation of postgan-glionic adrenergic nerve fibers that innervate arterioles and venules that occurs as an integral part of diabetic peripheral neuropathy (3). As a result, the adrenergic sympathetic...

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, instability of the internal sphincter probably plays a major role in incontinent diabetics (92). Another important cause is fecal impaction (93).

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). Chronic constriction injury, a model of neuropathic pain (51) likely develops from ischemia generated by the placement of four loose ligatures applied around a nerve trunk with gradual swelling and strangulation (52). To irreversibly damage axons acutely, ischemia must be severe and continuous for approximately 3 hours in nondiabetic peripheral nerves (50). Several important observations have emerged from these studies that are of relevance to the understanding of localized, or focal diabetic...

Studies In Animals

From Contemporary Diabetes Diabetic Neuropathy Clinical Management, Second Edition Edited by A. Veves and R. Malik Humana Press Inc., Totowa, NJ Evoked potentials are electrical field potentials as recorded on the scalp that are generated by specific brain structures in response to visual, auditory, or somatosensory stimuli. Measurements of the latencies of these evoked potentials can be used to study the efficiency of signal conduction in the brain, as a central equivalent of peripheral nerve conduction studies. As might be expected, in both STZ- and spontaneously diabetic rats the latencies of visual, auditory, and somatosensory evoked potentials are increased (14,15). However, unlike peripheral nerve conduction deficits, increases in evoked potential latencies take months, rather than weeks, to develop (14). Several of the metabolic and vascular disturbances that are implicated in peripheral neuropathy also appear to affect the brain (2,19). As in the periphery, excess glucose is...

Erectile Dysfunction

Diabetes was as high as in the older groups without diabetes (60-80 years). Thus, in presence of diabetes the development of ED starts around 20 years earlier than in the nondiabetic population. The crude incidence rate of ED in the MMAS was 26 cases 1000 man-years in 847 men aged 40-69 without ED at baseline who were followed for an average of 8.8 years (19). Population projections for men in this age group suggest an estimate of 617.715 new cases of ED per year for the United States. The age adjusted risk of ED was higher for men with lower education, diabetes, heart disease, and hypertension. The incidence rate of ED in men with diabetes was twofold increased, with 50 cases 1000 man-years. In a population based study from southern Wisconsin the prevalence of ED among 365 patients with type 1 diabetes increased with increasing age from 1.1 in those aged 21-30 years to 47.1 in those 43 years of age or older and with increasing duration of diabetes (20). In a study from Italy...

Outline Of Nervous Systems

One general design feature is found in all nervous systems above the level represented by the Porifera (sponges) and Cnidaria (jelly fish, sea anemones, hydroids). This is the separation of the nervous system into a central 'computing' region and a peripheral set of nerve fibres carrying information to and from the centre. In the chordates the 'central region', or central nervous system (CNS), consists of the brain and spinal cord (Figure 1.1), and the peripheral nervous system (PNS) consists of the cranial and spinal nerves.

Nerve Supply to the Pelvic Floor Autonomic Innervation

Cortical mapping with transcranial magnetic stimulation suggests that rectal and anal responses are bilaterally represented on the superior motor cortex, i.e., Brodmann area 4 16 . There are subtle differences in the degree of bilateral hemispheric representation between subjects. Motor neurons in Onufs nucleus, which is located in the sacral spinal cord, innervate the external anal and urethral sphincters. Though they supply striated muscles under voluntary control, these motor neurons are smaller than usual a-motor neurons and resemble autonomic motor neurons 17 however, the conduction velocity in pudendal nerve fibers is comparable with that of peripheral nerves. In contrast to other somatic motor neurons in the spinal cord, these neurons are relatively spared in amyotrophic lateral sclerosis but are affected in Shy-Drager syndrome 18, 19 . Somatic branches originating from Onuf's nucleus travel in the pudendal nerve, the muscular branches, and the coccygeal plexus. The pudendal...

Pathology and Histopathology

The CNS disease of FIV resembles those induced by HIV, and includes perivascular mononuclear cell infiltrates, glial nodules and diffuse gliosis of gray and white matter, and neuronal loss. Similar to HIV, neurotropic FIV strains infect microglia, astrocytes, and brain micro-vascular endothelial cells, but do not infect neuronal cells. Both anti-FIV antibodies and FIV virions have been isolated from cerebral spinal fluid (CSF) of infected cats, in addition to the elevated IgG index detected in the CSF. Like HIV, the level of FIV infection in the CNS cannot account for the cognitive motor function abnormalities observed in these cats, suggesting that cytokines induced during CNS infection may play a key role in FIV neuropathogenesis. Neurological abnormalities included limb paresis, delayed righting and pupillary reflexes, behavioral changes, delayed visual and auditory evoked potentials, decreased spinal and peripheral nerve conduction velocities, and sleep abnormalities (e.g.,...

Transmission and Tissue Tropism

Intranasal infection seems to be the most likely route of natural infection, since nerve endings in the nasal mucosa are readily accessible to the virus. Furthermore, certain pathological peculiarities observed in naturally infected horses, such as edema of the bulbus olfactorius, can be found in experimentally infected animals only after intranasal infection. Another possible route of infection might be orally, via the trigeminal nerve, which has been found to contain BDV-specific antigen in horses however, the possibility still exists that positive reactions in the nerve are rather due to early centrifugal spread of BDV via this nerve. In its natural hosts and also in adult experimentally infected animals the virus shows a strict neurotropism. After the virus has entered the nerves it migrates axonally to the central nervous system, where it replicates in neurons and astrocytes, especially in neurons of the hypothalamus. With time the virus spreads throughout the central nervous...

Clinical and Subclinical Infection

The pathogenesis of vCJD is distinct from other human prion diseases as there is evidence of significant involvement of peripheral tissues and in particular the lymphoreticular system, including lymph nodes, spleen, appendix, and tonsil, in addition to the central nervous system. Infectivity is also present in peripheral nerves and large intestine and PrPSc in enteric plexus, adrenal, ileum,

Vascular Contractility and Blood Flow

Hemodynamic abnormalities such as blood flow and vascular contractility have been reported in many organs of diabetic animals or patients, including the kidney, retina, peripheral arteries, and microvessels of peripheral nerves. In the retina of diabetic patients and animals with a short duration and without clinical retinopathy, blood flow has been shown to be decreased (119-123). One possible explanation for the decreased retinal blood flow in early stage of diabetes is as a result of an increase in vascular resistance at the microcirculatory level induced by PKC activation. We have reported that the decreased retinal blood flow can be mimicked by intravitreous injection of phorbol esters, which are PKC activators (78). Furthermore, decreases in retinal blood flow in diabetic rats have been reported to be normalized by PKC inhibitors (90). In addition to the retina, decreases in blood flow have also been reported in the peripheral nerves of diabetic animals by most investigators...

Pathogenic implications of NO deficiency

Vascular deficiency of NO may be critical for pathogenesis of micro and macrovascular complications of non-controlled diabetes mellitus (15). This may be appreciated in the light of physiological importance of basal activity of NO in maintaining an appropriate arteriolar vasodilation, stabilizing platelets and preventing excessive activation and circulating leucocyte adhesion (15). Loss of such activity may clearly promote ischaemia by inducing arteriolar vasoconstriction and microvascular occlusion by activated adhering leucocytes and thrombosis (15). Besides, NO increases sodium-potassium pump activity in arterial wall and in axons of peripheral nerve (15). Reduction of sodium-potassium pump activity in endothelial capillary cells exposed to hyperglycemia could, in the same way, be attributed to a lesser production of NO (15).

Sensorimotor Examination

Parkinson's disease, and normal pressure hydrocephalus. Dysarthria would alert the clinician to possible extrapyramidal disorders, bilateral strokes, de-myelinating disease, and motor neuron disease. Sensory abnormalities (e.g., peripheral neuropathy) may be associated with B12, other vitamin deficiency states, thyroid disease, or a paraneoplastic syndrome. Cerebellar signs might raise concerns about cerebrovascular disease, spinocerebellar degeneration, a paraneoplastic syndrome, and Creutzfeldt-Jakob disease. In Alzheimer's disease, especially early in its course, the sensorimotor examination tends to be relatively benign. Some researches have pointed out that the presence of extrapyramidal signs in patients with a profile otherwise consistent with Alzheimer's disease suggests a worse prognosis (33). Extrapyramidal signs may indicate the presence of Lewy body variant of AD (34). In general, if a patient with dementia presents with focal or multifocal neurological signs, the...

Essential Blepharospasm

TREATMENT The most affective treatment currently available is chemodenervation with botulinum toxin. The latter blocks neuromuscular transmission by inhibiting release of acetyl choline at peripheral nerve endings. Onset is usually within three to five days, and the duration of effect is typically about three months. For the 4 to 5 of patients who do not respond to botulinum toxin type A (Botox ) or who develop resistance to it, botulinum toxin type B (Myobloc ) is also available, and generally works well in most cases. When chemodenervation fails to give adequate results pharmacological agents such as benzodiazepines or anticholinergic agents can be added. For those who do not obtain satisfactory control of spasms on these regimens, surgical myectomy with removal of orbicularis muscle from the upper eyelids combined with brow fixation, will usually produce acceptable results.

Myelin And Myelination

Myelin is formed in both central and peripheral nervous systems by glial cells. In the peripheral nervous system the glial cells responsible are the Schwann cells. In the central nervous system (CNS) oligodendroglial cells perform the same task. The myelination process is, however, different in the two cases. Peripheral axons become associated with a sequence of single Schwann cells which form a In the CNS the process is different. Instead of a single Schwann cell being associated with a single axon it is found that single oligodendroglial cells myelinate many, sometimes up to fifty, different axons. This is achieved by the oligodendroglial cells sending out huge extensions of their plasma membranes, sometimes as much as ten times the diameter of their own cell bodies, which wrap around neighbouring axons to form their myelin sheaths (Figure 7.15). This is perhaps the most remarkable instance of membrane synthesis known. Oligodendroglial cells may synthesise up to three times their...

The Muscarinic Acetylcholine Receptor mAChR

Acetylcholine (ACh) (Figure 8.18) was the first neurotransmitter to be discovered - by Loewi in 1922 (see Box 16.2). ACh, or cholinergic, synapses exist in both the peripheral and central nervous systems. In the peripheral nervous system of vertebrates the neuromuscular junction is always cholinergic and it was here that the pharmacology of ACh was first investigated. We shall look further at this pharmacology in Chapter 16.

Virus Transmission among Individuals

Shedding are virus yield (from the standpoint of the virus, the more shedding the better) and timeliness of yield (again, the earlier the shedding the better). Viruses that cause persistent infections often employ remarkable means to avoid host inflammatory and immune responses so as to continue shedding. For example, the epidemiologically important shedding of herpes simplex viruses 1 and 2 that perpetuates the viruses in populations requires recrudescence of persistent ganglionic infection, centrifugal viral genomic transit to peripheral nerve endings and productive infection of mucosal epithelium, all in the face of established host immunity.

Etiology of Fecal Incontinence

Several neurologic disorders interfere with either sensory perception or motor function or both. Central nervous system disorders that may cause incontinence include multiple sclerosis, dementia, stroke, brain tumors, sedation, and dorsal and spinal cord lesions or injury 31-34 . Peripheral nervous system disorders include diabetic neuropathy, cauda equina lesions, alcohol-induced neuropathy, or traumatic neuropathy 33, 35, 36 .

Description Medical Diabetes

Long-term complications such as disease of the large and small blood vessels lead to cardiovascular disease (coronary artery disease, peripheral vascular disease, hypertension), retinopa-thy, and renal failure. Diabetic patients also have nerve damage (neuropathy) that can affect the peripheral nerves, resulting in numbness and pain of the hands or feet.

Pharmacologic Highlights

Explain that all cuts and blisters need to be cleaned and treated with an antiseptic preparation. If a cut or blister begins to appear infected (warmth, pain, swelling) or has drainage, encourage the patient to notify the primary healthcare provider immediately. Teach the patient to avoid constricting clothing such as constricting stockings, garters, girdles, or elastic slippers. If the patient needs to be on bedrest, encourage her or him to keep bed linens loose over the feet and legs. Instruct the patient to avoid very hot baths if peripheral neuropathy causes decreased temperature sensation.

PrV as a Tool in Neurobiology

Like other alphaherpesviruses, PrV exhibits a distinct neurotropism, invading the CNS via peripheral nerves. While wild-type strains of PrV may spread within the CNS both laterally and transsynaptically, attenuated PrV mutants have been identified which, under appropriate assay conditions, travel more or less exclusively along nerves and are transported transsynaptically. This property has prompted increasing use of PrV as a transneuronal tracer to label neuronal connections in experimental animal models, and has been useful in elucidating detailed neuroanatomical networks in mice and rats. The virus used most frequently in these studies is the Bartha strain of PrV, a modified-live vaccine strain which had been attenuated by the Hungarian veterinarian Adorjan Bartha by multiple passages in embryonated chicken eggs and chicken embryo fibroblasts. Molecular biological analyses demonstrated that this strain carries several lesions compared to wild-type PrV it lacks the gE, gI, and US9...

Autonomic Nervous System

It would be convenient and satisfying to be able to point out a particular part of the central nervous system and related peripheral nerves in insects that might comprise this regulatory system however, outside existing evidence that the meso- and or metathoracic ganglia play a major role in certain of these functions, entomologists know of no such discrete structure or structures, possibly because these interregulatory functions have been undertaken by different parts of the nervous system in different insects. It is known that insects have a number of regulatory mechanisms that can be recruited to achieve such control, from motor and sensory neurons to neurosecretory neurons to neurohormonal organs located all over the insect hemocoel.

Neuropsychiatric Systemic Lupus Erythematosus

In 1992, the ACR published a committee report on classification and case definitions of NPSLE. These case definitions were published in an appendix to the main article and are presented here in complete form. The committee recommended a basic demographic form for case-reporting purposes that is not included here. The syndromes can be subdivided into 19 syndromes encompassing both peripheral nervous system manifestations and CNS syndromes. Each of the guidelines is based on criteria with

Which Tests in Which Condition

In Table 2, a proposed schema of an integrated diagnostic workup is presented. From a general point of view, ARM and rectal sensation assessment should be considered mandatory in almost every clinical condition, being widely performed in coloproctolog-ical laboratories, moderately time consuming, and allowing considerable useful information. However, even if ARM could show a pressure pattern of sphincter asymmetry, it is not enough to diagnose a sphincter lesion therefore, integration with other diagnostic tests is mandatory. Rectal sensation assessment should be useful to eventually identify alterations due to central or peripheral neuropathy, metabolic diseases (i.e., diabetes), or radiotherapy given for pelvic neoplasms (situated at the anus, rectum, prostate, bladder, or gynecological organs). Finally, but not negligibly, other procedures could be needed to assess specific problems proctoscopy in FI due to rectal prolapse (eventual proctitis or solitary ulcer), rectal resection...

Pathways of the CNS Invasion

Viruses have been shown to enter the nervous system both along nerves and from the blood. The first experimental studies of viral invasion employed rabies, herpes simplex, or polioviruses, all of which, under experimental circumstances, can penetrate the nervous system along peripheral nerves. The precise mechanisms of neural spread remained a mystery for many years, since it was thought that the axoplasm slowly oozed in an anterograde direction. It was proposed that virus might move in perivascular lymphatics, by ascending infection of the supportive cells within the peripheral nerve, or even by replication in axons, a speculation that is now untenable because of the observed lack of ribosomes or protein synthesis within axons. In the 1960s active anterograde and retrograde axon transport systems were found. Viruses or other particles can be taken up in vesicles at the nerve terminals and transported to the cell body ofthe sensory or motor neuron (Figure 1). This neural route of...

Rehabilitative Techniques

Electrical stimulation can induce muscle contraction by direct stimulation or indirectly via peripheral nerve stimulation. Anal electrical stimulation can be used to treat fecal incontinence, and the rehabilitative cycle is performed daily for some months by the patient in the home environment 19 . Patients are instructed to self-administer electrical stimulation with an anal plug probe. The device delivers a square wave of current alternating between a work period of a few seconds and a double rest period, according to a standard sequence. The daily routine is modulated on a program based on (1) current pulse (width in milliseconds and frequency in hertz) and (2) duration (minutes day) and frequency (number day) of sessions.

Primary Disorders of HDL Metabolism

This disorder of HDL metabolism is autosomal recessive and very rare. Patients have a very low HDL level, elevated triglycerides, and low LDL levels. Clinically, the disorder is detected in childhood or early adulthood during a routine physical exam or during assessment of a sore throat because of the typical large orange tonsils. These patients also manifest a peripheral neuropathy, hepatosplenomegaly and premature coronary artery disease (8).

Significance of the aTocopherol Salvage Pathway

Vitamin E is present in plants in 8 different forms with essentially equal antioxidant potential (a-, P-, y-, S-tocopherol tocotrienols) nevertheless, in higher organisms only a-tocopherol is preferentially retained suggesting a specific evolutionary reason for the selective uptake of this analogue. In the last 20 years, the route of the tocopherols from the diet into the body has been clarified and the proteins involved in the uptake and selective retention of a-tocopherol discovered. Cellular functions of the tocopherols that are independent of their antioxidant radical scavenging abilities have been characterized in recent years. Vitamin E inhibits protein kinase C (PKC), protein kinase B (PKB), tyrosine kinases, 5-lipoxygenase and phospholipase A2 and activates protein phosphatase 2A, and diacylglycerol kinase. A growing number of genes are modulated by the tocopherols at the transcriptional level. The tocopherols also inhibit cell proliferation, platelet aggregation,...

How is Vitamin E Taken up and Distributed in the Body

Vitamin E uptake and metabolism. A) Uptake of vitamin E in higher organisms. The four tocopherols are taken up from the diet with equal efficiency (average 30 ) via the intestine and distributed to peripheral tissues by chylomicrons (Cm). In the course of chylomicron lipolysis, a part of the vitamin E is distributed to peripheral tissues, and the liver with the chylomicron remnants captures the other part. Chylomicron remnants (CmR) are taken up by the liver the a-tocopherol is recognized, sorted and secreted with VLDL. The remaining tocopherols and excess a-tocopherol is metabolized by the cytochrome P450 (CYP3A) enzyme, a phase I enzyme recognizing foreign compounds 21 . Part of the liver tocopherols (up to 14 ) is also secreted with bile, up to 60 of biliary a-tocopherol is reabsorbed, thus possibly undergoing a second chylomicron cycle 22,23 . In the liver a-TTP selectively recognizes a-tocopherol and incorporates it into VLDL. During circulation in the blood, VLDL...

Pathology and Pathogenesis

Enlarged peripheral nerves are present in almost all chickens with clinical signs of classical MD and in many with the acute form of the disease (Fig. 2). Figure 5 Lymphoid cell infiltration in peripheral nerve of a chicken with Marek's disease. (From Payne (1972), in Oncogenesis and Herpesviruses, Biggs, P.M., de The, G., and Payne L.N. (eds), pp. 21-37, IARC Scientific Publications No. 2, International Agency for Research on Cancer, Lyon, with permission.) Figure 5 Lymphoid cell infiltration in peripheral nerve of a chicken with Marek's disease. (From Payne (1972), in Oncogenesis and Herpesviruses, Biggs, P.M., de The, G., and Payne L.N. (eds), pp. 21-37, IARC Scientific Publications No. 2, International Agency for Research on Cancer, Lyon, with permission.) Affected nerves are usually two or three times their normal thickness, those commonly affected being the lumbosacral and brachial plexuses, the sciatic and brachial trunks and the celiac plexus. Two main pathological processes...

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.

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