Marker Of Peripheral Neuropathy Research Articles

124-OR: Progressive Loss of Corneal Nerve Fibers and Sensitivity with Duration of Obesity Type 2 Diabetes in Sprague-Dawley Rats: Valid Marker for Peripheral Neuropathy and Treatment

Purpose: Determine whether density of nerve fibers in the cornea and corneal function are valid markers for early detection and treatment of peripheral neuropathy in rat models of prediabetes and type 2 diabetes. Methods: Rat models for prediabetes and type 2 diabetes were created and longitudinally studied for loss of structure and function of sensory nerves in the cornea and skin as well as nerve conduction velocity and vascular reactivity of epineurial arterioles. Reversibility of neuro and vascular pathology was also examined in these models following chronic obesity or type 2 diabetes after dietary intervention with menhaden oil a natural source of long chain omega-3 polyunsaturated fatty acids. Results and Conclusions: Our longitudinal study demonstrated that vascular and neural dysfunction associated with obesity or type 2 diabetes occur early and are progressive. Decrease in cornea nerve fiber length and function were valid markers of disease in both the prediabetic and diabetic rat models and were more sensitive than decrease in intraepidermal nerve fiber density of the skin and thermal nociception of the hindpaw. Late intervention with menhaden oil reversed both vascular and peripheral damage induced by chronic obesity or type 2 diabetes. These studies provide support for examination of corneal structure and function as an early marker of peripheral neuropathy in prediabetes and diabetes. Furthermore, we demonstrate that omega-3 polyunsaturated fatty acids derived from fish oil as an effective treatment for peripheral neuropathy that occurs with chronic obesity or type 2 diabetes. Disclosure M.A. Yorek: Consultant; Self; Novo Nordisk Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK107339); U.S. Department of Veterans Affairs (RX000889)

Progressive Loss of Corneal Nerve Fibers and Sensitivity in Rats Modeling Obesity and Type 2 Diabetes Is Reversible with Omega-3 Fatty Acid Intervention: Supporting Cornea Analyses as a Marker for Peripheral Neuropathy and Treatment.

PurposeTo determine whether cornea nerve fiber density and/or corneal function are valid markers for early detection and treatment of peripheral neuropathy in rats modeling prediabetes and type 2 diabetes.MethodsHigh-fat feeding combined without or with low-dose streptozotocin was used to create rat models for prediabetes and type 2 diabetes that were longitudinally studied for loss of structure and function of sensory nerves in the cornea and skin as well as nerve conduction velocity and vascular reactivity of epineurial arterioles. There were three time points examined in each of the three conditions with 12 rats per group. The latest time point (24 weeks of high-fat diet with or without 16 weeks of hyperglycemia) was used to examine reversibility of neuro and vascular pathology following 16 weeks of treatment with menhaden oil, a natural source of long-chain omega-3 polyunsaturated fatty acids. The number of rats in the intervention study ranged from 6 to 17.ResultsOur longitudinal study demonstrated that vascular and neural dysfunction associated with obesity or type 2 diabetes occur early and are progressive. Decrease in cornea nerve fiber length and function were valid markers of disease in both the pre-diabetic and diabetic rat models and were more sensitive than decrease in intraepidermal nerve fiber density of the skin and thermal nociception of the hindpaw. Late intervention with menhaden oil significantly reversed both vascular and peripheral nerve damage induced by chronic obesity or type 2 diabetes.ConclusionThese studies provide support for examination of corneal structure and function as an early marker of peripheral neuropathy in prediabetes and type 2 diabetes. Furthermore, we demonstrate that omega-3 polyunsaturated fatty acids derived from fish oil are an effective treatment for peripheral neuropathy that occurs with chronic obesity or type 2 diabetes.

Advances in Confocal Microscopy of the Eye.

This special issue focuses on the recent advances on in vivo confocal microscopy (IVCM), a technique used to investigate eye structures at the cellular level without tissue damage. In 1985 Lemp and coworkers were the first to study ex vivo corneas by confocal microscopy and to suggest a possible in vivo use [1]. In the early 1990s, the groups directed by Cavanagh and Kaufman published the first IVCM in humans; thereafter the scientific interest in ocular IVCM rapidly increased. In the last decade, IVCM progressively gained a relevant role in the clinical setting, being of help in the diagnosis and management of a number of conditions such as toxicity induced by preservatives [2, 3] and different eye treatments [4, 5], iatrogenic damage [6], infections [7], and dystrophies [8], pathology of the conjunctiva [9–11] and limbus [12], ocular surface tumors [13], and corneal deposits [14, 15]. IVCM is a valuable tool for enhancing our understanding of anterior segment physiology and pathology, as pointed out by Dr. V. Fasanella et al. in their paper investigating meibomian gland changes occurring with aging and a number of ocular surface diseases. Examples of the usefulness of IVCM in detecting early corneal changes can be found in the paper by Dr. D. Wang et al., who highlighted that a higher-than-normal immune activity may be observed in a subgroup of patients with clear corneal grafts in the absence of any other clinical signs. Dr. P. Song et al. studied the confocal and histopathological features of the stromal scar in keratoconus and suggested that IVCM is capable of detecting subtle keratocyte activation associated with fibrosis. In recent years, IVCM has become increasingly useful in evaluating corneal innervation (which is of key importance in regulating ocular surface homeostasis) [16] and corneal immune and inflammatory responses [17]. In this special issue, three papers explored the changes occurring in corneal innervation in both local and systemic diseases. The paper by Dr. E. F. Wang et al. reviewed the impact of various systemic diseases on corneal innervation and discussed the potential use of IVCM as a noninvasive marker of peripheral neuropathy. The reports by Dr. R. Shetty et al. and Dr. N. K. Pahuja et al. investigated nerve changes occurring, respectively, in dry eye disease and keratoconus. Finally, IVCM plays a role in studying the therapeutic effects of topical eye treatments, as shown in this issue by the paper of Dr. A. M. Fea et al. This special issue provides a useful update on the advances in the rapidly evolving field of IVCM and highlights the contribution of this technology to our understanding of the anterior segment in health and disease. Paolo Fogagnolo Michele Iester Hong Liang Dipika V. Patel

Dioscorea Extract (DA-9801) Modulates Markers of Peripheral Neuropathy in Type 2 Diabetic db/db Mice

Dioscorea Extract (DA-9801) Modulates Markers of Peripheral Neuropathy in Type 2 Diabetic db/db Mice

Use of a novel high-resolution magnetic resonance neurography protocol to detect abnormal dorsal root Ganglia in Sjögren patients with neuropathic pain: case series of 10 patients and review of the literature.

The diagnosis and treatment of patients with Sjögren syndrome (SS) with neuropathic pain pose several challenges. Patients with SS may experience unorthodox patterns of burning pain not conforming to a traditional “stocking-and-glove” distribution, which can affect the face, torso, and proximal extremities. This distribution of neuropathic pain may reflect mechanisms targeting the proximal-most element of the peripheral nervous system—the dorsal root ganglia (DRG). Skin biopsy can diagnose such a small-fiber neuropathy and is a surrogate marker of DRG neuronal cell loss. However, SS patients have been reported who have similar patterns of proximal neuropathic pain, despite having normal skin biopsy studies. In such cases, DRGs may be targeted by mechanisms not associated with neuronal cell loss. Therefore, alternative approaches are warranted to help characterize abnormal DRGs in SS patients with proximal neuropathic pain.We performed a systematic review of the literature to define the frequency and spectrum of SS peripheral neuropathies, and to better understand the attribution of SS neuropathic pain to peripheral neuropathies. We found that the frequency of SS neuropathic pain exceeded the prevalence of peripheral neuropathies, and that painful peripheral neuropathies occurred less frequently than neuropathies not always associated with pain. We developed a novel magnetic resonance neurography (MRN) protocol to evaluate DRG abnormalities. Ten SS patients with proximal neuropathic pain were evaluated by this MRN protocol, as well as by punch skin biopsies evaluating for intraepidermal nerve fiber density (IENFD) of unmyelinated nerves. Five patients had radiographic evidence of DRG abnormalities. Patients with MRN DRG abnormalities had increased IENFD of unmyelinated nerves compared to patients without MRN DRG abnormalities (30.2 [interquartile range, 4.4] fibers/mm vs. 11.0 [4.1] fibers/mm, respectively; p = 0.03). Two of these 5 SS patients whose neuropathic pain resolved with intravenous immunoglobulin (IVIg) therapy had improvement of MRN DRG abnormalities.We have developed a novel MRN protocol that can detect DRG abnormalities in SS patients with neuropathic pain who do not have markers of peripheral neuropathy. We found that SS patients with MRN DRG abnormalities had statistically significant, increased IENFD on skin biopsy studies, which may suggest a relationship between trophic mediators and neuropathic pain. Given that our literature review has demonstrated that many SS neuropathic pain patients do not have a neuropathy, our findings suggest an important niche for this MRN DRG technique in the evaluation of broader subsets of SS neuropathic pain patients who may not have underlying neuropathies. The improvement of MRN DRG abnormalities in patients with IVIg-induced remission of neuropathic pain suggests that our MRN protocol may be capturing reversible, immune-mediated mechanisms targeting the DRG.

Alpha adrenoceptor agonist-induced microcirculatory oscillations are reduced in diabetic neuropathy

In diabetic patients small fiber neuropathy has been associated with impairment of 0.1 Hz microvascular vasomotion. The aim of this study was (1) to investigate whether vasoconstriction-induced microvascular oscillations in the skin are reduced in diabetic patients with peripheral and/or autonomic neuropathy, and (2) whether this method could be used as a non-invasive surrogate marker to assess diabetic small fiber neuropathy. Four matched groups were studied: diabetic patients without neuropathy (D), with peripheral neuropathy (DPN), with peripheral and autonomic neuropathy (DAN), and non-diabetic controls (Ctrl). All participants were evaluated for peripheral and autonomic neuropathy, microvascular endothelial function, and metabolic syndrome indicators. Laser Doppler flowmetry was used to measure oscillations after iontophoresis of the alpha one selective agonist phenylephrine. ~ 0.1-Hz oscillations recorded at the foot were significantly attenuated in diabetic patients with peripheral and/or autonomic neuropathy (DPN and DAN groups) compared to diabetic patients without neuropathy or non-diabetic controls. In the forearm, microvascular oscillations were significantly reduced only in patients with autonomic neuropathy (DAN). Oscillation measures correlated significantly ( P < 0.001) with all markers of peripheral neuropathy but not with markers of measurements of microvascular endothelial function, or metabolic syndrome markers. In a logistic regression model, reduced microvascular oscillations at the foot were a strong predictor for the presence of peripheral neuropathy. The measurement of phenylephrine-induced ~ 0.1-Hz microvascular oscillation may represent a useful non-invasive tool with which to study the effects of treatment strategies on the diabetic small fiber neuropathy.

WIN 55,212-2 prevents mechanical allodynia but not alterations in feeding behaviour induced by chronic cisplatin in the rat

Anorexia, nausea/emesis and peripheral sensorial neuropathy are frequent adverse effects associated with chemotherapy. Cannabinoids have been proposed to alleviate these effects, but their preventive properties in long-term experimental models have not been tested. This study was conducted to determine whether or not a cannabinoid agonist (WIN-55,212-2) can prevent anorexia, pica (an indirect marker of nausea in non-vomiting species, consisting of the ingestion of non-nutritive substances such as kaolin) and mechanical allodynia (a marker of peripheral neuropathy) induced by the antineoplastic drug cisplatin chronically administered. Isolated rats with free access to food and kaolin received either saline, cannabinoid vehicle, WIN-55,212-2 (1–2 mg kg − 1 ), cisplatin (1–2 mg kg − 1 ), or both drugs once per week for five consecutive weeks. Modifications in temperature, body weight gain, food and kaolin intake, and the threshold for mechanical allodynia were recorded. Additionally, the acute psychoactive effects of the cannabinoid (hypomotility, hypothermia, analgesia and catalepsia) were assayed by means of the cannabinoid tetrad. WIN 55,212-2 prevented the development of mechanical allodynia but not anorexia, pica and reduction in weight gain induced by chronic cisplatin. The effect of WIN 55,212-2 was evident even at a dose lacking activity in the cannabinoid tetrad. The preventive effect on cisplatin-induced mechanical allodynia exerted by the cannabinoid could be due to a neuroprotective role, as has been suggested for other conditions. The present results support the interest in the evaluation of cannabinoids for treatment of patients suffering or likely to suffer neuropathic pain.