Most Effective Peripheral Neuropathy Home Remedies

Peripheral Neuropathy Solution By Dr. Randall Labrum

Neuropathy Solution is considered as a self- treatment program that supplies people with a proven, simple solution for peripheral neuropathy. Randall Labrum, the author of this program claims that his treatment works successfully for most cases without fail, no matter your peripheral neuropathy results from chemotherapy, diabetes, hypertensions, or aging process. The program reveals to people some useful ways to end their chronic diabetic nerve pain fast and naturally. Moreover, the program can help people resolve their diabetic nerve and peripheral neuropathy pain in both legs and feet, and hands and arms. After Randall Labrum launched Peripheral Neuropathy Solution program, a lot of clients have benefited from using it. You can effectively heal your neuropathy and achieve optimal health. With the Neuropathy Solution Program, you do not need to squander more money and time on surgery and drugs, as well as other methods that do not function. Many people have benefited from this program. If you give it a try, you too can gain those benefits. Read more here...

The Peripheral Neuropathy Solution Overview

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All of the information that the author discovered has been compiled into a downloadable pdf so that purchasers of The Peripheral Neuropathy Solution can begin putting the methods it teaches to use as soon as possible.

When compared to other e-books and paper publications I have read, I consider this to be the bible for this topic. Get this and you will never regret the decision.

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...

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...

End Points For Clinical Trials In Diabetic Neuropathy

Among the challenges for studies of diabetic neuropathy is the selection of the measures that can be used to determine the efficacy of the agents. Common end points include 2. Questionnaires that allow for quantification of any changes in the symptoms of diabetic neuropathy, or the quality of life of the patient (e.g., neuropathy symptom scores, total neuropathy scores). The following summarizes the view of prospective end points in diabetic neuropathy trials Mechanisms for Pathogenesis of Diabetic Neuropathy and Therapies That Have Been Tested Addressing Them Mechanisms for Pathogenesis of Diabetic Neuropathy and Therapies That Have Been Tested Addressing Them

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,...

Disorders of movement mononeuropathy

Diabetic neuropathy can affect nerves to individual muscles. The result is a sudden inability to move or use those muscles, called mononeuropathy. These disorders are believed to originate as a result of a sudden closing of a blood vessel supplying the nerve. The clinical picture depends on which nerve or nerves are affected. For example, if one of the nerves to the eyeball is damaged, the patient can't turn his eye to the side that nerve is on. If a nerve to the face is affected, the eyelid may droop or the smile on one side of the face may be flat. The patient with mononeuropathy can have trouble with vision or problems with hearing. Focusing the eye may not be possible. There's no specific treatment for mononeuropathy, but fortunately the disorder goes away on its own after several months.

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...

Peripheral neuropathy

Problems that arise are numbness so that rubbing or injury is not noticed, loss of temperature discrimination with a risk of burning, loss of position sense which, if severe, can make walking and balance difficult. Loss of vibration sense is an early sign of neuropathy but has no major clinical impact. This peripheral neuropathy may be accompanied by tingling or actual pain.

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...

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.

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...

Microangiopathy Diabetes And The Peripheral Nervous System Experimental Studies

Neuropathy Peripheral Nervous System

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

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...

Spinal Cord Involvement In Diabetic Neuropathy

Previously considered a disease of the peripheral nervous system (PNS), there is mounting evidence to support concomitant involvement of the CNS in diabetic neuropathy. Involvement of the spinal cord has been reported in post-mortem studies, which demonstrated axonal loss, gliosis, and demyeli-nation within the spinal cord (2-6). However, many of these studies did not examine patients with diabetic neuropathy specifically therefore, it is not possible to conclude whether these changes were due to neuropathy or diabetes. The reason why some patients develop painful neuropathic symptoms is far from clear. These can occur with little objective evidence of peripheral nerve dysfunction and can be extremely distressing and difficult to treat. Electrical spinal cord stimulation has been used to alleviate pain, which is unresponsive to conventional treatment (7). However, it has been observed that this technique is ineffective in subjects with severe loss of vibration and joint position...

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...

Sonic Hedgehog And Diabetic Neuropathy

Mechanism Diabetic Neuropathy

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

How do you diagnose peripheral diabetic neuropathy

Special tests (nerve conduction velocity and quantitative examinations of nerve function) are not necessary for the diagnosis in routine clinical practice. A study in the USA found that around 10 percent of diabetics had peripheral neuropathy due to another cause, other than DM. Table 15.1. Causes of peripheral neuropathy Consequently, before neuropathy can be attributed to DM, other causes need to be ruled out. These causes of peripheral neuropathy are described in Table 15.1.

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,...

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...

Therapies Targeting Autoimmunity

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

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).

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).

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...

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...

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...

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...

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...

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...

Diabetic Foot Ulceration

Diabetic Foot Ulcer Process Formation

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...

Pathophysiology Of Microvascular Disease And Endothelial Dysfunction In Diabetes

Pathophysiology Diabetic Polyneuropathy

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...

Lowpa In Vivo Studies On Receptor Pharmacology

Comparison of distal sympathetic with vagal function in diabetic neuropathy. Muscle Nerve 1986 9 592-596. 15. Rundles RW. Diabetic neuropathy. General review with report of 125 cases. Medicine 1945 24 111-160. 19. Palumbo PJ, Elveback LR, Whisnant JP. Neurologic complications of diabetes mellitus transient ischemic attack, stroke, and peripheral neuropathy. AdvNeurol 1978 19 593-601. 65. Low PA. Quantitation of autonomic function, in Peripheral Neuropathy (Dyck, PJ, Thomas, PK, Lambert, EH, and Bunge, R, eds.), WB Saunders, Philadelphia, 1984, pp. 1139-1165. 69. Maselli RA, Jaspan JB, Soliven BC, Green AJ, Spire JP, Arnason BGW. Comparison of sympathetic skin response with quantitative sudomotor axon reflex test in diabetic neuropathy. Muscle Nerve 1989 12 420-423. 72. Soliven B, Maselli R, Jaspan J, et al. Sympathetic skin response in diabetic neuropathy. Muscle Nerve 1987 10 711-716. 73. Braune HJ, Horter C. Sympathetic skin response in diabetic...

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....

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...

Vasoregulation Of Somatic Nerve Fibers

Vasoregulation

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

Correlation Between Epidermal Nerve And Sural Nerve

Diabetes Cutaneous Nerve Fibers

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 electrophysio-logical 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...

Charcot Neuroarthropathy

Common Feet Deformities

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

Underlying Metabolic Abnormalities In Type And Type

Growth And Metabolic Abnormalities

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).

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...

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...

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...

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...

Structural Abnormalities In Type And Type

Diabetic Neuropathy Myelinated Axon

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...

Gastroduodenal Dysfunction The Gastroparesis Syndrome

Ballondilatation Pylorus

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...

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...

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...

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...

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...

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...

Diabetic Foot Formalin

Eaton SE, Harris ND, Rajbhandarim SM, et al. Spinal-cord involvement in diabetic peripheral neuropathy. Lancet 2001 358 35-36. 7. Woltman HW, Wilder RM. Pathologic changes in the spinal cord and peripheral nerves. Arch Intern Med 1929 44 576-603. 8. Dolman CL. The morbid anatomy of diabetic neuropathy. Neurology 1963 13 135-142. 9. Olsson Y, S ve-S derbergh J, Sourander P, Angervall L. A patho-anatomical study of the central and peripheral nervous system in diabetes of early onset and long duration. Path Europ 1968 3 62-79. 11. Reske-Nielsen E, Lundbaek K. Pathological changes in the central and peripheral nervous system of young long-term diabetics. Diabetologia 1968 4 34-43. 13. Greenbaum D, Richardson PC, Salmon MV, Urich H. Pathological observations on six cases of diabetic neuropathy. Brain 1964 87 201-214. 23. Jakobsen J. Earlyt and preventable changes of peripheral nerve structure and function in insulin-deficient diabetic rats. J Neurol Neurosurg Psychiatr 1979 42 509-518. 28....

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...

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...

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).

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

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,...

Role For Nonenzymatic Glycation

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

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...

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...

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...

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...

Summary

Peripheral neuropathy is a devastating complication of diabetes mellitus because of the debilitating symptoms it causes or associated higher risk of other complications, in particular those involving the lower extremity. This chapter will review the prevalence, incidence, and risk factors for different types of diabetic neuropathy. There are seven major types of diabetic neuropathy (1) distal symmetric polyneuropathy, (2) autonomic neuropathy, (3) nerve entrapment syndromes, (4) proximal asymmetric mononeuropathy (also known as diabetic amyotrophy), (5) truncal radiculopathy, (6) cranial mononeuropathy, and (7) chronic inflammatory demyelinating polyradiculopathy (CIDP). This chapter will focus mainly on the first two types of neuropathy, but will review the available data on the epidemiology of the other types of neuropathy. 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...

Type Dm Vs Type 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...

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...

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...

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.

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...

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...

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...

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....

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...

Clinical Deficits

Michigan Diabetic Neuropathy Score

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...

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).

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...

Erectile Dysfunction

Neuroendocrine Control Penile Erection

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...

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...

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...

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.

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...

Quantitative sensory testing

The limitations of QST are also clear. No matter what the instrument or procedure used, QST is only a semiobjective measure, affected by the subject's attention, motivation and cooperation, as well as by anthropometric variables such as age, sex, body mass and history of smoking and alcohol consumption (Gerr & Letz 1994 Gelber et al. 1995). Expectancy and subject bias are additional factors that can exert a powerful influence on QST findings (Dyck et al. 1998). Further, QST is sensitive to changes in structure or function along the entire neuroaxis from nerve to cortex it is not a specific measure of peripheral nerve function (Arezzo 2003). QST testing for vibratory and cooling thresholds receives a class II rating as a diagnostic test. It is designated as safe, effective and established. Thus QST is accepted and commonly used in clinical trials of diabetic neuropathy.

Conclusions On Treatment

Although considerable improvement in the quality of controlled trials has recently been achieved, no major breakthrough in slowing the progression of diabetic neuropathy in the long run has been achieved with drugs used on the basis of present pathogenetic concepts. Some of the newer drugs have shown promising results in phase II trials which require confirmation from large phase III trials. It is conceivable that drugs interfering with the pathogenesis of diabetic neuropathy may be most effective in terms of prevention, rather than intervention. Although several novel analgesic drugs have recently been introduced into clinical practice, the pharmacologic treatment of chronic painful diabetic neuropathy remains a challenge for the physician. Individual tolerability remains a major aspect in any treatment decision. Almost no information is available from controlled trials on long-term analgesic efficacy and only a few studies have used drug combinations. Combination drug use or the...

Recent Developments

A recent randomized, double-blind, placebo-controlled study3 compared the efficacy of a combination of gabapentin and morphine with that of each as a single agent in patients with painful diabetic neuropathy or post-herpetic neuralgia. Patients received daily active placebo, sustained-release morphine, gabapentin, or a combination of gabapentin and morphine each given orally for five weeks. Of 57 patients who underwent randomization (35 with diabetic neuropathy and 22 with post-herpetic neuralgia), 41 completed the trial. Mean daily pain (on a scale from 0 to 10, with higher numbers indicating more severe pain) was rated as follows 5.72 at baseline, 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin-morphine combination (P < 0.05). Total scores on the Pain Questionnaire (on a scale from 0 to 45, with higher numbers indicating more severe pain) at a maximal tolerated dose were 14.4 with placebo, 10.7 with gabapentin, 10.7 with morphine, and 7.5...

Pathogenetic Mechanisms

Recent experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. Most data have been generated in the diabetic rat model, on the basis of which two approaches have been chosen to contribute to the clarification of the pathogenesis of diabetic neuropathy. Firstly, it has been attempted to characterize the pathophysiological, pathobiochemical, and structural abnormalities that result in experimental diabetic neuropathy. Secondly, specific therapeutic interventions have been employed to prevent the development of these alterations, to halt their progression, or to induce their regression despite concomitant hyperglycemia. At present, the following six pathogenetic mechanisms are being discussed which, however, in contrast to previous years are no longer regarded as separate hypotheses but in the first place as a complex interplay with multiple interactions between metabolic and vascular factors

Patients with complicated diabetes

Insulin has been used in patients with severe painful diabetic neuropathy, even if their glycaemic balance approximates to normal on oral therapy. The rationale is that aggressive normalization of the blood glucose with insulin may relieve the symptoms. Patients with other tissue damage may benefit.

Clinical Presentation Of

The symptoms of DAN are often very subtle and insidious in onset and may be unrecognized. Alternatively, because the symptoms of DAN can be so diverse and reproduce the appearance of many other disease processes, the patient may be subjected to extensive diagnostic evaluation without reward. In common with other forms of diabetic neuropathy, DAN is essentially a diagnosis of exclusion. The most prominent clinical signs and symptoms of autonomic involvement complicating diabetes include the gastrointestinal tract system, cardiovascular system, bladder, sex organs, ocular pupil, sweat glands, and adrenal medullary system. The clinical presentations of this multiple-organ involvement are discussed in the following sections.

Increased Aldose Reductase Activity

The aldose reductase pathway has been extensively studied because of the presence of the enzyme in the retina, kidney, and nerves. These are all targets for the long-term complications and would present a unified model for the damage caused by chronic hyperglycemia. The enzyme increases its activity in the presence of high blood glucose levels and causes increased levels of sorbitol. Sorbitol dehydrogenase metabolizes the sorbitol that is then postulated to lead to other metabolic changes that can cause neuropathy and retinopathy. This pathway has been best studied in relation to diabetic neuropathy (8). Despite this understanding of the possible underlying role for this mechanism, trials of aldose reductase inhibitors in slowing down the development or progression of retinopathy and neuropathy have not been very effective.

Corneal Confocal Microscopy CCM

Density, branching and tortuosity in patients with mild diabetic neuropathy, and these alterations relate to the severity of somatic neuropathy (Malik et al. 2003 Kallinikos et al. 2004). Corneal nerve fibre density has recently been shown to improve with improved glycaemic control (Iqbal et al. 2005). Therefore, the ability of CCM to visualise and define the extent of nerve damage and repair occurring in diabetic patients is significant (Hossain et al. 2005). The noninvasive facility of CCM provides a means of expediting drug development programmes for therapies deemed to be beneficial in the treatment of diabetic peripheral neuropathy.

Screening For Diabetic Complications

Symptoms of sensory, motor and autonomic neuropathy should be documented at the time of diagnosis of diabetes and reassessed at least every 6 months. Other neurological conditions must be ruled out before a diagnosis of diabetic neuropathy is made. The patient should be informed that symptoms of diabetic neuropathy may improve slowly with improved glycaemic control.

Disorders of sensation

Distal polyneuropathy is the most frequently occurring form of diabetic neuropathy. Distal means far away from the center of the body, like the feet and hands. Poly means many, and neuropathy is disease in nerves. So this is a disease of many nerves noticed in the hands and feet. The most serious complication of loss of sensation in the feet is the neuropathic foot ulcer. A person with normal nerve function feels pain when pressure mounts on an area of the foot. However, a person with diabetic neuropathy doesn't feel this pressure. A callus forms, and with continued pressure, the callus softens and liquefies, finally falling off to leave an ulcer. This ulcer becomes infected. If it isn't promptly treated, it spreads, and amputation may be the only way to save the patient. In this situation, loss of blood supply to the feet isn't an important contributing factor to the ulceration in fact, the blood supply may be good, but an ulcer still develops.

Disorders of automatic autonomic nerves

Even as you're reading this page, many movements of muscles are going on inside your body, but you're unaware of them. Your heart muscle is squeezing down and relaxing. Your diaphragm is rising up to empty the lungs of air and relaxing to draw air in. Your esophagus is carrying food from the mouth to the stomach and, in turn, the stomach pushes it into the small intestine, which pushes it into the large intestine. All these muscle functions are under the control of nerves from the brain, and diabetic neuropathy can affect all of them. These automatic functions are called the autonomic nerves. Sensitive tests determine that as many as 40 percent of people with diabetes have some form of autonomic neuropathy.

Treatments targeting the ARpolyol pathway

Numerous experimental and clinical studies with different ARI have implicated the diabetes-induced increased flux of glucose through the polyol pathway in the development of diabetic retinopathy and neuropathy however, only a few studies have investigated the influence of ARI in diabetic kidney. Sorbinil, tolrestat and ponalrestat have been withdrawn from clinical trials due to toxicity or a lack of efficacy in human diabetic neuropathy,76 although ponalrestat has a positive effect on renal hyperfiltration in type 1 diabetic patients.77

Should asymptomatic bacteriuria be treated in diabetic individuals

Factors that have been incriminated in the increased incidence of ASB in diabetic women are hyperglycaemia (and the resultant disturbance of leukocytes' function), poor glycaemic control, more frequent use of urinary bladder catheters (as is observed in diabetics), presence of autonomous nervous system neuropathy and relapsing vaginal infections, as well as the more frequent presence of anatomic abnormalities (also observed in diabetics) such as cystocoele, cystourethrocoele and recto-coele. It appears that the presence of diabetic neuropathy has particular importance. Decreased sensation of the urinary bladder leads to its distention, urinary retention and increased residual urine volume, resulting in an increased sensitivity towards infections as well as the appearance of infections with a smaller initial number of pathogenic micro-organisms. A 62 year old woman was brought to the hospital because of fever and pain in the left lower extremity. The symptoms had begun two days prior...

Symptomatic treatments

They do not have formal FDA approval for this condition. Although cheap and generally efficacious in the management of neuropathic pain, side effects limit their use in many patients. Tricylcic drugs may also exacerbate some autonomic symptoms such as gastroparesis. Gabapentin is a commonly prescribed anticonvulsant that has been shown to be efficacious in the treatment of neuropathic pain 19 , although not approved for this condition. It is advisable to start at a small dose and then increase over days to weeks to the dosage that is well tolerated and produces symptomatic relief. The structurally-related compound pregabalin is longer acting, has also been confirmed to be useful in painful diabetic neuropathy, and is approved for use in this condition 20, 21 . Other anticonvulsant drugs may also be efficacious in the management of neuropathic pain. The 5-hydroxytryptamine and norepinephrine reuptake inhibitor duloxetine has been approved by the FDA for treatment of neuropathic pain 22...

Entrapment neuropathies

You can see that you can run into all kinds of problems if you develop diabetic neuropathy. None of them need ever bother you, though, if you follow the recommendations in Part III the closest you will ever get to a nerve problem will be when you try to get a date with that cute neighbor.

Early indications of kidney disease

Recent evidence suggests, however, that an abnormal amount of albumin in the urine is not always present when diabetic neuropathy is developing. A study in Diabetes Care in January 2004 showed that as many as 25 percent of people with diabetes have kidney disease even though there is no increase in the albumin in their urine. Blood tests for kidney function show some loss of function, yet the test for increased albumin is negative. In other words, the absence of microalbuminuria does not always indicate that no kidney damage is taking place. Rather, this finding suggests that treatment with drugs that protect the kidneys should be done for all patients with diabetes, not just those with microalbuminuria.

How is the followup done of individuals with DM who carry an insulin pump

As regards glycaemic control, the results are controversial. Some studies support the idea that treatment with pumps has an advantage and other studies show that the two treatments are equivalent. There is, however, a general consensus that the blood glucose fluctuations are smaller with the use of a pump, and the hypoglycaemic episodes are fewer. Moreover, a claimed increase in the percentage of ketoacidotic episodes with pump users, compared to those treated with multiple insulin injections, has not been proven. A lot of small studies agree that quality of life is better when a pump is used, and that microvascular complications occur less often. There is also evidence that diabetic neuropathy is improved with the use of an insulin pump.

What should be done with regard to the glycaemic control of this patient

A 63 year old-man has suffered from Type 2 DM for 20 years. He has received isophane insulin (NPH) for three years, 26 units in the morning and 16 units in the evening. His control is moderate (the HbA1c level during the previous year ranged from 7.5 percent to 8.1 percent). One month ago he underwent a coronary artery bypass operation, after a myocardial infarction that he had suffered three months before. After the operation, he continued the same DM treatment. His body weight is normal (weight 74 kg 163.2 lb , height 1.72 m 5 ft 7.7 in , BMI 25kg m2). Recent laboratory evaluation showed a slightly increased creatinine level (1.5 mg dl 132.6 mmol L ). There exists background diabetic retinopathy and diabetic neuropathy. He reports that after the surgery his blood sugar control is worse than ever and he often manifests hyperglycaemic symptoms, despite the fact that he is particularly diligent with his diet. The latest HbA1c is 8.8 percent. He brings a diary with blood sugar...

Risk Factors For Stroke In Diabetic Subjects

Other DM-specific stroke risk factors are microvascular complications and diabetic neuropathy. Patients with retinopathy are at increased risk of predominantly lacunar stroke (59, 60) but see (61) , and post-stroke mortality is increased (62-64). The relation between stroke and retinopathy is more evident in type 2 than type 1 DM (32), but this may be due to the age of the patients who were studied. Proteinuria may also be an independent risk factor for stroke (65, 66), but the relation between the degree of proteinuria (microalbuminuria or macroalbuminuria) and the level of the risk of stroke is not yet clear (32, 66, 67), and some studies failed to reveal a significant association between albuminuria and the risk of stroke or stroke mortality

Minimizing foot trauma

It is essential to consider the health of the feet of the patient prior to engaging in exercise or physical activity, this is especially important for patients with peripheral neuropathy. Appropriate footwear, socks and care of feet before and after the exercise bout is important. Daily visual checks by the patient and regular checks by a health professional are also important (Chipkin et al., 2001 ADA, 2002). Furthermore, weight bearing exercise may not be appropriate for some patients with severe peripheral neuropathy.

Supporting evidence is of classes A B R

Neuropathy - Peripheral neuropathy is difficult to prevent and treat. Most patients with type 2 diabetes and peripheral neuropathy have few symptoms but are found on examination to have diminished reflexes and sensation. Sometimes neuropathy can be very painful, especially at night, with pins-and-needles numbness and tingling in a stocking-and-glove distribution. Absence of reflexes or decreased thermal, vibratory, proprioceptive or pain sensation may be noted on examination and confirm the diagnosis. Good glycemic control should be the first control to symptomatic neuropathy. Treatment with amitrip-tyline, nortriptyline, or trazodone in doses beginning at 25 mg at night and increasing to 75 mg may help some patients. Topical treatment with capsaicin, 0.025 cream three to four times per day, has also shown benefit. Carbamazepine, duloxatine and gabapentin may improve neuropathic pain also. These medications may provide symptomatic relief, but they do not improve the neuropathy...

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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