J. Robinson Singleton

Painful sensory polyneuropathy associated with impaired glucose tolerance

We examined records of 121 patients coded as idiopathic polyneuropathy, extracting neuropathy symptoms, electromyographic data, and diagnostic blood work. Of 89 patients screened for glucose handling, 28 demonstrated frank diabetes mellitus. Of the remaining 61 patients, 15 (25%) had impaired glucose tolerance (IGT) by American Diabetes Association criteria (serum glucose 140–200 mg/dl 2 h after a 75‐g glucose load). Excluding those with diabetes mellitus, 35% of patients with neuropathic pain had IGT, more than twice the prevalence found in large, unselected population studies. No other common etiology of polyneuropathy was identified. Two‐hour oral glucose tolerance test results were often abnormal, whereas fasting glucose or hemoglobin A1c was normal. Bias due to referral pattern, body weight, or genetics might affect the comparison of our polyneuropathy cohort with a broader, population‐based control. However, our results corroborate an association between IGT and painful sensory polyneuropathy and link these patients syndromically to the typical painful polyneuropathy of diabetes mellitus.

Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy.

The authors describe skin biopsy findings in patients with peripheral neuropathy associated with diabetes and impaired glucose tolerance (IGT). Six patients with IGT, eight with early diabetes-associated neuropathy, and five controls were recruited. Most subjects underwent nerve conduction studies (NCS) and quantitative sensory tests (QST). Skin biopsy was abnormal in all neuropathy subjects and correlated poorly with NCS. Neuropathy associated with IGT primarily affects small fibers and is similar to early diabetes-associated neuropathy.

Type I Insulin-like Growth Factor Receptor Activation Regulates Apoptotic Proteins

Activation of the type I insulin-like growth factor receptor (IGF-IR) blocks osmotic mediated programmed cell death (PCD) in neurons. We speculated that IGF-IR activation could afford neuroprotection either by effecting the negative regulators of the death pathway, Bcl-2 and Bcl-xL, or by altering activity of the ced-3/ICE-like proteases. Here we report that osmotic stress decreases total neuronal Bcl-2 by 4-fold and that hyperosmotic PCD correlates with proteolytic processing of neuronal ced-3/ICE-like proteases. IGF-IR activation maintains normal Bcl-2 levels, and signaling via the IGF-IR:phosphatidylinositol 3-kinase pathway prevents ICE/LAP-3 and Yama/CPP32 processing. Finally, increased neuronal IGF-IR expression enhances the negative death regulator Bcl-xL. We suggest that IGF-IR signaling exerts its short-term inhibitory effects upon PCD “upstream” of both Bcl proteins and ced-3/ICE-like proteases, while chronic increased IGF-IR expression may modulate susceptibility to death signals by mediating the negative death regulator, Bcl-xL.

Impaired glucose tolerance and neuropathy.

Background:Peripheral neuropathy is common. Diabetes is the most common cause, accounting for approximately half of cases, but up to 1/3rd of neuropathy patients have no identifiable etiology. Among this population, impaired glucose tolerance (IGT or “prediabetes”) is observed in approximately 40%. The exact nature of the relationship between IGT and neuropathy is debated. Review Summary:A variety of evidence suggests IGT causes neuropathy. Neuropathy may occur early in diabetes. The neuropathy associated with IGT is clinically similar to early diabetic neuropathy, with preferential injury to small nerve fibers resulting in pain and autonomic dysfunction. IGT and diabetic neuropathy patients share abnormal microvascular endothelial dysfunction. Treatment of IGT subjects with diet and exercise reduces risk of progression to diabetes, and those with neuropathy experience a short-term improvement in small fiber function with sustained benefit for pain. An evolving literature links other aspects of the metabolic syndrome to peripheral neuropathy. Conclusions:IGT is common in peripheral neuropathy patients. The extent to which IGT directly causes nerve injury as opposed to being a covariant with other equally or more important features (eg, obesity, metabolic syndrome) remains to be determined. Preliminary data suggest diet and exercise counseling may be a useful treatment strategy.

The reliability of skin biopsy with measurement of intraepidermal nerve fiber density

Intraepidermal nerve fiber density (IENFD) is a sensitive measure of small fiber injury, and holds promise as a clinical trial endpoint measure. A total of 48 punch biopsies were obtained from 22 patients. Tissue was sectioned and stained with PGP9.5. The relative intertrial variability (RIV) of IENFD measurements for each section and punch made by two different observers was determined (interobserver variability). Intraobserver variability (same observer measuring twice) was determined for 50% of the sections and punches. Sections from 12 punch biopsies were also stained at a second laboratory. The effect of the number of sections counted and processing site on reproducibility was investigated. A total of 223 sections were analyzed. The mean IENFD was 6.7 fibers/mm. Mean (+/-standard deviation) interobserver variability was 9.6%+/-9.4 for each biopsy site and 10.2%+/-11.9 for individual sections. Mean intraobserver variability was 9.6%+/-8.9 for biopsies, and 8.8%+/-9.0 for sections. There was no significant difference in IENFD for tissue stained at different laboratories. Intraclass correlation coefficients were greater than 0.98 for each comparison. There was no relationship between absolute IENFD and reproducibility. Reproducibility was highest when four sections were counted. IENFD measurement is highly reproducible. At least four sections should be analyzed. Reliability does not vary with severity of disease. These findings suggest IENFD may be a useful endpoint measure in future neuropathy treatment trials.

The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy.

Abstract  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.

Idiopathic neuropathy patients are at high risk for metabolic syndrome

BACKGROUND Idiopathic neuropathy patients are at high risk of impaired glucose tolerance (IGT). Hyperglycemia, low high density lipoprotein (HDL), elevated triglycerides (TRG), hypertension and central obesity co-associate and constitute the metabolic syndrome. Patients with hyperglycemia are at high risk of having the syndrome and each of its features. Our null hypothesis was that patients with neuropathy and IGT would have a higher prevalence of other metabolic syndrome features than those without hyperglycemia. The primary objective was to determine if metabolic syndrome features other than hyperglycemia increase neuropathy risk. METHODS The prevalence of metabolic syndrome features was determined among 219 sequential patients with idiopathic peripheral neuropathy. Subjects were classified as having IGT or normoglycemia. The prevalence of metabolic syndrome was compared to published population prevalence data. To compensate for potential referral bias, data were also compared for175 diabetic subjects without neuropathy, given the well-recognized risk of metabolic syndrome among diabetic individuals. RESULTS Contrary to our hypothesis, neuropathy patients with normoglycemia and IGT shared a similarly elevated prevalence of metabolic syndrome features compared to published normal populations. Compared to diabetic subjects without neuropathy, the normoglycemic neuropathy patients had significantly higher total and LDL cholesterol, and a higher prevalence of abnormal HDL and triglycerides. The prevalence of obesity and hypertension was similar among patient groups. Normoglycemic neuropathy subjects had significantly more features of metabolic syndrome (other than hyperglycemia) than diabetics. CONCLUSIONS These findings demonstrate an association between neuropathy and metabolic syndrome features other than hyperglycemia. Lipid abnormalities are particularly prevalent among neuropathy subjects.

Obesity and hyperlipidemia are risk factors for early diabetic neuropathy

The Utah Diabetic Neuropathy Study (UDNS) examined 218 type 2 diabetic subjects without neuropathy symptoms, or with symptoms of<5 years, in order to evaluate risk factors for neuropathy development. Each subject completed symptom questionnaires, the Utah Early Neuropathy Scale (UENS), nerve conduction studies (NCS), quantitative sensory testing (QST) for vibration and cold detection, quantitative sudomotor axon reflex testing (QSART), and skin biopsy with measurement of intraepidermal nerve fiber density (IENFD). Those with abnormalities of≥3 were classified as having probable, and those with 1-2 as possible neuropathy. The relationship between glycemic control, lipid parameters (high density lipoprotein and triglyceride levels), blood pressure, and obesity, and neuropathy risk was examined. There was a significant relationship between the number of abnormalities among these features and neuropathy status (p<0.01). Hypertriglyceridemia, obesity and 3 or more abnormalities increased neuropathy risk (risk ratios 2.1 p<0.03, 2.9 p>0.02 and 3.0 p<0.004 respectively). Multivariate analysis found obesity and triglycerides were related to loss of small unmyelinated axons based on IENFD whereas elevated hemoglobin A1c was related to large myelinated fiber loss (motor conduction velocity). These findings indicate obesity and hypertriglyceridemia significantly increase risk for peripheral neuropathy, independent of glucose control. Obesity/hypertriglyceridemia and hyperglycemia may have differential effects on small versus large fibers.

The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy

AIMS Diagnosis of early distal symmetric polyneuropathy (DSP) is challenging. Nerve conduction studies (NCS) are often normal. Skin biopsy for intraepidermal nerve fiber density (IENFD) has better sensitivity, but is invasive. Sudoscan is a novel technology that measures electrochemical skin conductance (ESC; microSiemens, μS), which is thought to be proportionate to the number of functional sweat glands. This study evaluated Sudoscans diagnostic utility for DSP. METHODS 55 patients with suspected DSP (22 with diabetes, 2 prediabetes, 31 idiopathic) and 42 controls underwent the Utah Early Neuropathy Scale (UENS) and Sudoscan. Each was offered skin biopsy. DSP participants underwent quantitative sudomotor axon reflex testing (QSART) and NCS. RESULTS Feet and hands ESCs were reduced among DSP participants compared to controls (64±22 vs. 76±14 μS p<0.005, and 58±19 vs. 66±18 μS p<0.04). There was no difference between diabetic and idiopathic DSP. Receiver operating characteristic curve analysis revealed feet ESC and IENFD had similar areas under the curve (0.761 and 0.752). ESC correlated with Sural amplitude (0.337, p<0.02), UENS (-0.388, p<0.004), and MNSI (-0.398, p<0.005). CONCLUSIONS Sudoscan is a promising diagnostic test for diabetic and idiopathic DSP, with diagnostic performance similar to IENFD.

Reliability of Quantitative Sudomotor Axon Reflex Testing and Quantitative Sensory Testing in Neuropathy of Impaired Glucose Regulation

Reproducible neurophysiologic testing paradigms are critical for multicenter 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 multicenter research setting. Twenty‐three participants with neuropathy and IGR were recruited from two study sites. The reproducibility of quantitative sudomotor axon reflex test (QSART) and quantitative sensory test (QST) (using the CASE IV system) was determined in a subset of patients at two sessions, and it was calculated from intraclass correlation coefficients (ICCs). QST (cold detection threshold: ICC = 0.80; vibration detection threshold: ICC = 0.75) was more reproducible than QSART (ICC foot = 0.52). The performance of multiple tests in one setting did not improve reproducibility of QST. QST reproducibility in our IGR patients was similar to reports of other studies. QSART reproducibility was significantly lower than QST. In this group of patients, the reproducibility of QSART was unacceptable for use as a secondary endpoint measure in clinical research trials. Muscle Nerve, 2008