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Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). Methods:We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: "What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?" Results and Recommendations:Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL. Neurology Diabetic sensorimotor polyneuropathy represents a diffuse symmetric and length-dependent injury to peripheral nerves that has major implications on quality of life (QOL), morbidity, and costs from a public health perspective.1,2 Painful diabetic neuropathy (PDN) affects 16% of patients with diabetes, and it is frequently unreported (12.5%) and more frequently untreated (39%).3 PDN presents an ongoing management problem for patients, caregivers, and physicians. There are many treatment options available, and a rational approach to treating the patient with PDN requires an understanding of the evidence for each intervention.This guideline addresses the efficacy of pharmacologic and nonpharmacologic treatments to reduce pain and improve physical function and QOL in patients with PDN. The pharmacologic agents reviewed include anticonvulsants, antidepressants, opioids, anti-arrhythmics, cannabinoids, aldose reductase inhibitors, protein kinase

In vivo regeneration of peripheral neurons is constrained and rarely complete, and unfortunately patients with major nerve trunk transections experience only limited recovery. Intracellular inhibition of neuronal growth signals may be among these constraints. In this work, we investigated the role of PTEN (phosphatase and tensin homolog deleted on chromosome 10) during regeneration of peripheral neurons in adult Sprague Dawley rats. PTEN inhibits phosphoinositide 3-kinase (PI3-K)/Akt signaling, a common and central outgrowth and survival pathway downstream of neuronal growth factors. While PI3-K and Akt outgrowth signals were expressed and activated within adult peripheral neurons during regeneration, PTEN was similarly expressed and poised to inhibit their support. PTEN was expressed in neuron perikaryal cytoplasm, nuclei, regenerating axons, and Schwann cells. Adult sensory neurons in vitro responded to both graded pharmacological inhibition of PTEN and its mRNA knockdown using siRNA. Both approaches were associated with robust rises in the plasticity of neurite outgrowth that were independent of the mTOR (mammalian target of rapamycin) pathway. Importantly, this accelerated outgrowth was in addition to the increased outgrowth generated in neurons that had undergone a preconditioning lesion. Moreover, following severe nerve transection injuries, local pharmacological inhibition of PTEN or siRNA knockdown of PTEN at the injury site accelerated axon outgrowth in vivo. The findings indicated a remarkable impact on peripheral neuron plasticity through PTEN inhibition, even within a complex regenerative milieu. Overall, these findings identify a novel route to propagate intrinsic regeneration pathways within axons to benefit nerve repair.

The objective of this report was to develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). The basic question that was asked was: "What is the efficacy of a given treatment (pharmacological: anticonvulsants, antidepressants, opioids, others; non-pharmacological: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?" A systematic review of literature from 1960 to August 2008 was performed, and studies were classified according to the American Academy of Neurology classification of evidence scheme for a therapeutic article. Recommendations were linked to the strength of the evidence. The results indicate that pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence, or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness. Few studies have sufficient information on their effects on function and QOL.

Thirty patients with definite or probable chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) of chronic progressive (16 patients) or relapsing (14 patients) course were randomly assigned to receive intravenous immunoglobulin (IvIg) 0.4 g per kg body weight or a placebo treatment on 5 consecutive days in a double-blind, cross-over trial. Neurological function was monitored by serial quantitative assessments [neurological disability score (NDS); clinical grade (CG) and grip strength (GS) measurements] and by electrophysiological studies before and after each treatment period. Twenty-five patients completed both treatment periods. A comparison of the observed changes in clinical outcome measures revealed statistically significant differences in favour of IvIg, with (mean +/- SD) improvements in NDS by 24.4 +/- 5.4 points (P < 0.002) in CG by 1 +/- 0.3 points (P < 0.001) in GS by +6.3 +/- 1.7 kg (P < 0.005), whereas scores were unchanged or worse with placebo. A secondary two-groups analysis of the first trial period included all 30 patients; 16 patients had been randomly assigned to IvIg and 14 to placebo treatments. Again significant differences in favour of IvIg were observed in all the clinical end-points: improvement in NDS was 35.6 +/- 25 points (P < 0.0001), in CG it was 1.3 +/- 1.9 points (P < 0.002) and in GS +9.8 +/- 7.7 kg (P < 0.001), whereas all scores worsened with placebo. Of the 30 patients, 19 (63%) improved with IvIg treatments; nine out of 16 patients (56%) with chronic progressive CIDP, and 10 out of 14 patients (71%) with relapsing CIDP (differences were not statistically significant). A placebo response was seen in five patients. Comparison of paired electrophysiological measurements before and 4 weeks after IvIg treatments revealed statistically significant improvements in the summed motor conduction velocities (sigma MCV; P< -0.0001) and in the summed compound muscle action potentials (CMAP) evoked with proximal stimulation (sigma proximal CMAP, P < 0.03) of median, ulnar, peroneal and tibial nerves. Eight of nine IvIg responders with chronic progressive CIDP improved gradually to normal function with a single 5 day course of IvIg; in five of these, small doses of prednisone were prescribed during follow-up. In 10 IvIg responders with relapsing CIDP, improvements lasted a median 6 weeks (range 3-22 weeks) and was reproducible with open label treatments. All 10 patients have been maintained and stabilized with IvIg pulse therapy of 1 g per kg body weight or less, given as a single infusion prior to the expected relapse. A beneficial response to IvIg was found to be most likely in patients with acute relapse or with disease of one year or less. Patients with predominantly sensory signs did not improve.

Encephalopathy and polyneuropathy occur in 70% of septic patients. The encephalopathy is diffuse, appears early, is often severe, but reverses quickly with successful treatment of the sepsis. The electroencephalogram is a sensitive indicator of the incidence and severity of the encephalopathy, but computed tomograms of the brain and cerebrospinal fluid findings are unremarkable. Critical-illness polyneuropathy develops later and in association with multiple-organ failure. Recovery is more gradual. Difficulty in weaning from the ventilator is an important early manifestation. Electromyography should be routinely performed to establish the diagnosis. The polyneuropathy is a primary axonal degeneration, predominantly of distal motor fibers. A persistent deficit may eventuate in severe cases. Whether muscle is affected as consistently as brain and peripheral nerve, and by the same process, has not been determined. Medications used in critical care units, notably sedatives and neuromuscular blocking agents, often confuse the clinical picture. The neurological pathophysiology is unknown but current evidence suggests that nervous system dysfunction arises through the same mechanisms as for systemic organs in the septic syndrome.

Diabetic polyneuropathy is the most common acquired diffuse disorder of the peripheral nervous system. It is generally assumed that insulin benefits human and experimental diabetic neuropathy indirectly by lowering glucose levels. Insulin also provides potent direct support of neurons and axons, and there is a possibility that abnormalities in direct insulin signaling on peripheral neurons relate to the development of this disorder. Here we report that direct neuronal (intrathecal) delivery of low doses of insulin (0.1-0.2 IU daily), insufficient to reduce glycemia or equimolar IGF-I but not intrathecal saline or subcutaneous insulin, improved and reversed slowing of motor and sensory conduction velocity in rats rendered diabetic using streptozotocin. Moreover, insulin and IGF-I similarly reversed atrophy in myelinated sensory axons in the sural nerve. That intrathecal insulin had the capability of signaling sensory neurons was confirmed by observing that fluorescein isothiocyanate-labeled insulin given intrathecally accessed and labeled individual lumbar dorsal root ganglion neurons. Moreover, we confirmed that such neurons express the insulin receptor, as previously suggested by Sugimoto et al. Finally, we sequestered intrathecal insulin in nondiabetic rats using an antiinsulin antibody. Conduction slowing and axonal atrophy resembling the changes in diabetes were generated by anti-insulin but not by an anti-rat albumin antibody infusion. Defective direct signaling of insulin on peripheral neurons through routes that include the cerebrospinal fluid may relate to the development of diabetic peripheral neuropathy.