OBJECTIVE -The purpose of this study was to evaluate intraepidermal nerve fiber density (IENFD) as a sensitive measure of neuropathy change in patients with neuropathy associated with impaired glucose tolerance (IGT) receiving lifestyle intervention based on that used in the Diabetes Prevention Program.RESEARCH DESIGN AND METHODS -We performed 3-mm skin biopsies with measurement of IENFD at the distal leg and proximal thigh at baseline and after 1 year in 32 subjects with IGT. Each received individualized diet and exercise counseling as a standard of care. Nerve conduction studies, quantitative sensory testing, quantitative sudomotor axon reflex testing, and the Michigan Diabetic Neuropathy score were performed, and a visual analog pain scale was completed. Two-hour oral glucose tolerance tests (OGTTs) following the American Diabetes Association guidelines were performed, and serum lipid levels were measured at baseline and 1 year later.RESULTS -Baseline distal IENFD was 0.9 Ϯ 1.2 fibers/mm and proximal IENFD was 4.8 Ϯ 2.3 fibers/mm. Baseline distal IENFD correlated with fasting glucose (P Ͻ 0.001) and OGTT (P Ͻ 0.01). After 1 year of treatment, there was a 0.3 Ϯ 1.1-fiber/mm improvement in distal IENFD and a 1.4 Ϯ 2.3-fiber/mm improvement in proximal IENFD (P Ͻ 0.004). The change in proximal IENFD correlated with decreased neuropathic pain (P Ͻ 0.05) and a change in sural sensory amplitude (P Ͻ 0.03).CONCLUSIONS -These findings indicate that diet and exercise counseling for IGT results in cutaneous reinnervation and improved pain. Skin biopsy was the most sensitive measure of neuropathy change over 1 year. IENFD should be included as an end point in future neuropathy trials. Diabetes Care 29:1294 -1299, 2006I diopathic peripheral neuropathy is common. Population studies indicate that 5-14% of individuals Ͼ40 years old have neuropathy (1,2). Several groups have demonstrated a 40% prevalence of impaired glucose tolerance (IGT) among subjects with otherwise idiopathic neuropathy (3-5), compared with Ͻ15% in the age-matched general population (6). This observation supports the hypothesis that IGT-related neuropathy may represent the earliest stage of diabetic neuropathy. One practical test of this hypothesis is to determine whether treatment of IGT results in slowed progression of neuropathy. The Diabetes Prevention Program (DPP) demonstrated that intensive diet and exercise counseling slows progression of IGT to diabetes compared with placebo or metformin (7). We are studying patients with IGT and neuropathy in the Impaired Glucose Tolerance Neuropathy (IGTN) study, a National Institutes of Health-funded Clinical Pilot Project investigating the clinical features and progression of IGTN. As a standard of care, all IGTN study subjects receive diet and exercise intervention modeled on that used in the DPP.The neuropathy associated with IGT and early diabetes is sensory predominant and painful and is characterized by prominent small-fiber injury. The most sensitive diagnostic measure is skin biopsy with measurement of...

Early neuropathy is often sensory predominant and prominently involves small-diameter nerve fibers. Established neuropathy examination scales such as the Michigan Diabetic Neuropathy Scale (MDNS) and the Neuropathy Impairment Score-Lower Leg (NIS-LL) focus primarily on large-fiber sensory and motor function. Here, we validate the Utah Early Neuropathy Scale (UENS), a physical examination scale specific to early sensory predominant polyneuropathy. Compared with other scales, the UENS emphasizes severity and spatial distribution of pin (sharp) sensation loss in the foot and leg and focuses less on motor weakness. UENS, MDNS, and NIS-LL were compared in 215 diabetic or prediabetic subjects, with (129) or without neuropathy (86), and repeated in 114 neuropathy subjects after 1 year of follow-up. Neuropathy severity was also evaluated with nerve conduction studies, quantitative sensory testing, quantitative sudomotor axonal reflex testing, and intraepidermal nerve fiber density determination. The UENS had a high degree of interrater reliability (interclass correlation of 94%). UENS correlated significantly to MDNS and NIS-LL (p < 0.01), and more significantly than MDNS or NIS-LL to confirmatory tests. In this cohort, UENS had a superior profile to receiver operating characteristic analysis across a range of scores, with a sensitivity (92%) higher than MDNS (67%) or NIS-LL (81%), without sacrificing specificity. UENS more closely correlated with change in ancillary and small-fiber neuropathy measures over 1 year follow-up than did MDNS or NIS-LL. UENS is a sensitive and reproducible clinical measure of sensory and small-fiber nerve injury and may be useful in trials of early neuropathy.

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Reproducible neurophysiological testing paradigms are critical to multi-center studies of neuropathy associated with impaired glucose regulation (IGR), yet the best methodologies and endpoints remain to be established. This study evaluates the reproducibility of neurophysiologic tests within a multi-center research setting. Twenty-three participants with neuropathy and IGR were studied. Reproducibility of QSART and QST (using the CASE IV system) were determined in a subset of patients at two sessions and calculated from intraclass correlation coefficients (ICC). QST (cold detection threshold ICC 0.80, vibration detection threshold ICC 0.75) was more reproducible than QSART (ICC foot 0.52). Performing multiple tests in one setting did not improve reproducibility of QST. QST reproducibility in IGR patients is similar to other patient groups studied. QSART reproducibility was significantly lower than QST. In this group of patients, the reproducibility of QSART was unacceptable for a secondary endpoint measure in clinical research trials.

Lesions involving the intralaminar thalamic nuclei have been associated with impairments in working memory and intentional motor function in human clinical cases and animal models of amnesia. The intralaminar nuclei have afferent and efferent connections related to striatum. To test whether disruption of striatal function can account for impairments produced by intralaminar lesions, we investigated the effects of striatal lesions on two tasks known to be impaired by intralaminar damage in the rat: radial maze delayed nonmatching (DNM), a measure of spatial working memory, and self-paced serial reaction time (SRT), a measure of intentional response speed. We compared the effects of lesions in four sites: the medial and lateral caudate putamen, nucleus accumbens, and olfactory tubercle. We found that lesions of the medial, accumbens, or tubercle sites impaired DNM performance, and that lesions of the lateral caudate putamen increased choice response time for the SRT task. There was a double dissociation between the effects of the ventral and the lateral lesions on these two tasks. For both tasks, the effects of striatal lesions were qualitatively similar and at least as large as intralaminar lesions in previous studies. These results provide evidence that striatal dysfunction can account for the DNM and SRT impairments produced by intralaminar lesions. The dissociation of functional impairments suggests that lateral sensorimotor areas of caudate putamen are important for responding based on external sensory stimuli and limbic-related areas in ventral striatum are important for responding based on information held in working memory.