Douglas W. Zochodne

Evidence-based guideline: Treatment of painful diabetic neuropathy: Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation

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.

Multifocal motor neuropathy improved by IVIg Randomized, double-blind, placebo-controlled study

Objective: To determine the effect of IV immunoglobulin (IVIg) on neurologic function and electrophysiologic studies in multifocal motor neuropathy with conduction block (MMN). Background: MMN is characterized by progressive, asymmetric, lower motor neuron weakness and is probably immune-mediated. IVIg treatment has been shown to have beneficial effects in several open-label studies and in one small controlled trial. However, larger randomized controlled studies are lacking. Methods: The authors recruited 16 patients with MMN. All subjects were given each of two treatments (IVIg [0.4 g/kg/d for 5 consecutive days] or placebo [dextrose or saline]) that were assigned according to a randomized, crossover design under double-blind conditions. Patients were evaluated before and about 28 days after trial treatment for subjective functional improvement, neurologic disability score, grip strength, distal and proximal compound muscle action potential amplitude, and conduction block. Results: Subjective functional improvement with IVIg treatment was rated as dramatic or very good in nine patients, moderate in one, mild in one, and absent in five patients. This improvement was absent after placebo. The neurologic disability score improved by 6.7 ± 3.3 points with IVIg treatment, whereas it decreased by 2.1 ± 3.0 with placebo (p = 0.038). Grip strength on the weaker side was increased by 6.4 ±1.9 kg with IVIg treatment; it decreased by 1.0 ± 0.8 kg with placebo (p = 0.0021). Conduction block worsened by 12.98 ± 6.52 % with placebo, but improved by 12.68 ± 5.62 % with IVIg treatment (p = 0.037). Conduction block was reversed in five patients with IVIg but not placebo. Conclusion: IVIg improved conduction block as well as subjective and objective clinical measures of function in patients with MMN.

A decline in glial cell-line-derived neurotrophic factor expression is associated with impaired regeneration after long-term Schwann cell denervation.

In the peripheral nervous system, regeneration of motor and sensory axons into chronically denervated distal nerve segments is impaired compared to regeneration into acutely denervated nerves. In order to find possible causes for this phenomenon we examined the changes in the expression pattern of the glial cell-line-derived neurotrophic factor (GDNF) family of growth factors and their receptors in chronically denervated rat sciatic nerves as a function of time with or without regeneration. Among the GDNF family of growth factors, only GDNF mRNA expression was rapidly upregulated in Schwann cells as early as 48 h after denervation. This upregulation peaked at 1 week and then declined to minimal levels by 6 months of denervation. The changes in the protein expression paralleled the changes in the expression of the GDNF mRNA. The mRNAs for receptors GFRalpha-1 and GFRalpha-2 were upregulated only after maximal GDNF upregulation and remained elevated as late as 6 months. There were no significant changes in the expression of GFRalpha-3 or the tyrosine kinase coreceptor, RET. When we examined the expression of GDNF in a delayed regeneration paradigm, there was no upregulation in the distal chronically denervated tibial nerve even when the freshly axotomized peroneal branch of the sciatic nerve was sutured to the distal tibial nerve. This study suggests that one of the reasons for impaired regeneration into chronically denervated peripheral nerves may be the inability of Schwann cells to maintain important trophic support for both motor and sensory neurons.

Critical Illness Myopathy

Acute myopathy is a common problem in intensive care units. Those at highest risk for developing critical illness myopathy are exposed to intravenous corticosteroids and paralytic agents during treatment of various illnesses. Diffuse weakness and failure to wean from mechanical ventilation are the most common clinical manifestations. Serum creatine kinase levels are variable. Electrodiagnostic studies reveal findings of a myopathic process, often with evidence of muscle membrane inexcitability. Based on animal model studies, the loss of muscle membrane excitability may be related to inactivation of sodium channels at the resting potential. In addition, human and animal pathologic studies reveal characteristic loss of myosin with relative preservation of other structural proteins. In some patients, there is also upregulation of proteolytic pathways, involving calpain and ubiquitin, in conjunction with increased apoptosis. Fortunately, the disorder is reversible, but there may be considerable morbidity.

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

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.

Receptor for Advanced Glycation End Products (RAGEs) and Experimental Diabetic Neuropathy

OBJECTIVE— Heightened expression of the receptor for advanced glycation end products (RAGE) contributes to development of systemic diabetic complications, but its contribution to diabetic neuropathy is uncertain. We studied experimental diabetic neuropathy and its relationship with RAGE expression using streptozotocin-induced diabetic mice including a RAGE−/− cohort exposed to long-term diabetes compared with littermates without diabetes. RESEARCH DESIGN AND METHODS— Structural indexes of neuropathy were addressed with serial (1, 3, 5, and 9 months of experimental diabetes) electrophysiological and quantitative morphometric analysis of dorsal root ganglia (DRG), peripheral nerve, and epidermal innervation. RAGE protein and mRNA levels in DRG, peripheral nerve, and epidermal terminals were assessed in WT and RAGE−/− mice, with and without diabetes. The correlation of RAGE activation with nuclear factor (NF)-κB and protein kinase C βII (PKCβII) protein and mRNA expression was also determined. RESULTS— Diabetic peripheral epidermal axons, sural axons, Schwann cells, and sensory neurons within ganglia developed dramatic and cumulative rises in RAGE mRNA and protein along with progressive electrophysiological and structural abnormalities. RAGE−/− mice had attenuated structural features of neuropathy after 5 months of diabetes. RAGE-mediated signaling pathway activation for NF-κB and PKCβII pathways was most evident among Schwann cells in the DRG and peripheral nerve. CONCLUSIONS— In a long-term model of experimental diabetes resembling human diabetic peripheral neuropathy, RAGE expression in the peripheral nervous system rises cumulatively and relates to progressive pathological changes. Mice lacking RAGE have attenuated features of neuropathy and limited activation of potentially detrimental signaling pathways.

Diabetes mellitus and the peripheral nervous system: Manifestations and mechanisms

Diabetes targets the peripheral nervous system with several different patterns of damage and several mechanisms of disease. Diabetic polyneuropathy (DPN) is a common disorder involving a large proportion of diabetic patients, yet its pathophysiology is controversial. Mechanisms considered have included polyol flux, microangiopathy, oxidative stress, abnormal signaling from advanced glycation endproducts and growth factor deficiency. Although some clinical trials have demonstrated modest benefits in disease stabilization or pain therapy in DPN, robust therapy capable of reversing the disease is unavailable. In this review, general aspects of DPN and other diabetic neuropathies are examined, including a summary of recent therapeutic trials. A particular emphasis is placed on the evidence that the neurobiology of DPN reflects a unique yet common and disabling neurodegenerative disorder. Muscle Nerve, 2007

Axon and Schwann cell partnership during nerve regrowth.

Regeneration of peripheral nerve involves an essential contribution by Schwann cells (SCs) in collaboration with regrowing axons. We examined such collaboration between new axons and Schwann cells destined to reform peripheral nerve trucks in a regeneration chamber bridging transected rat sciatic nerves. There was a highly intimate “dance” between axons that followed outgrowing and proliferating SCs. Axons without SCs only grew short distances and almost all axon processes had associated SC processes. When regeneration chambers were infused through an external access port with local mitomycin, a mitosis inhibitor, SC proliferation, migration and subsequent axon regrowth were dramatically reduced. Adding laminin to mitomycin did not reverse this regenerative lag and indicated that SCs provide more than laminin synthesis alone. Laminin infused alone supplemented endogenous laminin and facilitated first SC then axon regrowth. “Wrong way” misdirected axons were associated with misdirected SC processes and were more numerous in bridges exposed to mitomycin, but were fewer in laminin supplemented bridges. Later, by 21 days, there was myelinated axon repopulation of regenerative bridges but those exposed to mitomycin alone at early time points had substantial impairments in axon investment. Reforming peripheral nerve trucks involves a very close and intimate relationship between axons and SCs that must proliferate and migrate, facilitated by laminin.

Local expression of inducible nitric oxide synthase in an animal model of neuropathic pain

Peripheral nerve injury is associated with local inflammation and neuropathic pain. In this study we investigated the local expression of the inducible isoform of nitric oxide synthase (iNOS) following a chronic constriction injury (CCI) to the sciatic nerve, a rat model of neuropathic pain. Western blot analysis and immunohistochemical co-localization methods were used to identify temporal and spatial expression of iNOS and its cells of origin. Changes in mRNA were analyzed by RT-PCR and iNOS specific primers. We report that CCI injury induced local iNOS expression in both macrophages and Schwann cells within and distal to the injury site. The local increase in iNOS mRNA expression paralleled both the temporal and spatial protein expression. This study supports the hypothesis that CCI is associated with a local inflammatory reaction mediated at least in part by iNOS. Local activation of the iNOS-NO system may play an important role in the pathogenesis of peripheral nerve injury and neuropathic pain.

Impaired peripheral nerve regeneration in diabetes mellitus

Abstract  Diabetes mellitus impairs peripheral nerve regeneration. Regenerative failure likely exacerbates deficits from polyneuropathy or focal neuropathies in patients who might otherwise exhibit spontaneous improvement. Some focal neuropathies, like carpal tunnel syndrome, are common, yet render ongoing disability because of their delayed recovery. Why diabetic nerves fail to regenerate is an interesting question to consider because several mechanisms likely contribute. In this review, we examine a number of these causes. These causes include microangiopathy or disease of small blood vessels, failure to provide proper metabolic support for repair, defects in the entry and actions of inflammatory cells within the injury milieu, less robust support of axons by their Schwann cells, and lack of a full repertoire of trophic factors. A number of the mechanisms that generate neuropathy in the first place also likely contribute to failed regenerative programs, but how they do so is not clear.