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...

We conducted a serological study to define correlates of immunity against SARS-CoV-2. Relative to mild COVID-19 cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against nucleocapsid (N) and the receptor binding domain (RBD) of spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months post-onset, whereas α-N titers diminished. Testing of 5882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.

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.

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.

We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.