A Gordon Smith

University of Utah, Salt Lake City, Utah, United States

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Publications (35)120.91 Total impact

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    ABSTRACT: Objective This study focused on altered mitochondrial dynamics as a potential mechanism for diabetic peripheral neuropathy (DPN). We employed both an in vitro sensory neuron model and an in situ analysis of human intraepidermal nerve fibers (IENFs) from cutaneous biopsies to measure alterations in the size distribution of mitochondria as a result of hyperglycemia and diabetes, respectively.Methods Neurite- and nerve-specific mitochondrial signals within cultured rodent sensory neurons and human IENFs were measured by employing a three-dimensional visualization and quantification technique. Skin biopsies from distal thigh (DT) and distal leg (DL) were analyzed from three groups of patients; patients with diabetes and no DPN, patients with diabetes and confirmed DPN, and healthy controls.ResultsThis analysis demonstrated an increase in mitochondria distributed within the neurites of cultured sensory neurons exposed to hyperglycemic conditions. Similar changes were observed within IENFs of the DT in DPN patients compared to controls. This change was represented by a significant shift in the size frequency distribution of mitochondria toward larger mitochondria volumes within DT nerves of DPN patients. There was a length-dependent difference in mitochondria within IENFs. Distal leg IENFs from control patients had a significant shift toward larger volumes of mitochondrial signal compared to DT IENFs.InterpretationThe results of this study support the hypothesis that altered mitochondrial dynamics may contribute to DPN pathogenesis. Future studies will examine the potential mechanisms that are responsible for mitochondrial changes within IENFs and its effect on DPN pathogenesis.
    Annals of Clinical and Translational Neurology. 09/2014;
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    ABSTRACT: 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, microSimens – uS), which is thought to be proportionate to the number of functional sweat glands. This study evaluated Sudoscan’s 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 ESC were reduced among DSP participants compared to controls (64 +/- 22 vs. 76 +/- 14 uS p < 0.005, and 58 +/- 19 vs. 66 +/- 18 uS 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.
    Journal of diabetes and its complications 01/2014; · 2.11 Impact Factor
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    ABSTRACT: To evaluate the reproducibility of in vivo confocal microscopy for quantitative corneal nerve analysis in different corneal locations. Corneal confocal microscopy was performed on 10 healthy participants, and the corneal nerve fiber length, corneal nerve fiber density, corneal nerve branch density, and tortuosity coefficient were measured at 5 predetermined locations for only the right eye. Bland-Altman plots, intraclass correlation coefficient (ICC), and coefficient of variation of all 4 corneal nerve measurements were compared between 2 visits and between readers to assess reproducibility. Two technicians performed a masked analysis of images from both visits. Ten participants with a mean age of 31.3 ± 2.8 years were imaged at 2 different time points separated by a mean of 4.3 ± 4.3 weeks. The interobserver agreements were better than the intervisit agreements for all the 4 corneal nerve measurements as evaluated using Bland-Altman plots. The intervisit ICC ranged from 0.13 to 0.45, and the interobserver ICC ranged from 0.55 to 0.94. The differences between observers and the differences between sessions were not statistically different among all the 5 locations (P > 0.1) for each corneal nerve measurement. Single confocal images have poor reliability for any of the 4 corneal nerve measurements, and there is no single location on the cornea that has improved reproducibility. Averaging 5 images, from different locations, improves the reproducibility and is essential for obtaining clinically meaningful data.
    Cornea 08/2013; · 1.75 Impact Factor
  • A Gordon Smith, J Robinson Singleton
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    ABSTRACT: The Utah Diabetic Neuropathy Study (UDNS) examined 218 type 2 diabetic subjects without neuropathy symptoms, or with symptoms of<5years, 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.
    Journal of diabetes and its complications 05/2013; · 2.11 Impact Factor
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    ABSTRACT: We examined changes in intraepidermal nerve fibers (IENFs) to differentiate patients with diabetic neuropathy (DN) and diabetic neuropathic pain (DN-P) from those with DN without pain (DN-NOP). Punch skin biopsies were collected from the proximal thigh (PT) and distal leg (DL) of normal subjects, patients with type 2 diabetes without evidence of DN (DM), or DN-P and DN-NOP patients. Protein gene product 9.5-positive (PGP+) immunohistochemistry was used to quantify total IENF, and growth-associated protein 43 (GAP43) for regenerating IENF. Compared to normal subjects and patients with type 2 diabetes without evidence of DN, both DN-P and DN-NOP have reduced PGP+ IENF densities in DL and PT. Although GAP43+ IENF densities were also reduced in DL for both DN-P and DN-NOP, the GAP43+ IENF densities in PT of DN-P remained at the control levels. Higher GAP43/PGP ratios were detected in DN-P compared to DN-NOP in the DL and PT. In parallel, increased numbers of axonal swellings per PGP+ fiber (axonal swelling/PGP) were detected in DN-P compared to normal subjects, patients with type 2 diabetes without evidence of DN, and DN-NOP in the DL. These axonal swellings were positive for tropomyosin-receptor-kinase A and substance P, suggesting that they are associated with nociception. PERSPECTIVE: Among patients with DN, the ratios of GAP43/PGP and axonal swelling/PGP are likely to differentiate painful from painless phenotypes.
    The journal of pain: official journal of the American Pain Society 05/2013; · 3.78 Impact Factor
  • Ted M Burns, A Gordon Smith
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    ABSTRACT: The assessment of intraepidermal nerve fiber density (IENFD) can be an objective, valid, and useful tool for the diagnosis of small-fiber neuropathy. IENFD testing involves sampling a small area of epidermis; a reduced IENFD relative to published age and sex normal values aids the diagnosis of small-fiber neuropathy. Patients often have borderline values, however, raising concerns of sampling bias, human error, and technical variations. In this issue of Neurology(®), Engelstad et al.(1) report on efforts to refine the sampling process and the analytical protocol for IENFD assessment. The investigators obtained 3-mm skin punch biopsies from the distal leg and proximal thigh in healthy participants and patients with diabetes mellitus. Processed specimens were cut into 50-μm sections, taking 10 serial "skip sections" (sections 5, 7, 9, 11-23) for analysis. The epidermal nerve fibers/mm were counted by one technician and audited for accuracy by another. The variability of IENFD among sections was calculated for different numbers of sections counted (e.g., 4 vs 10 sections evaluated). The more sections reviewed, the lower the variability in IENFD (figure 1 of their article). While not surprising, this result is important because it suggests the number of sections to be quantified might need to be tailored for each patient, thus increasing reliability. Most laboratories currently base IENFD on measurement of 4 sections.(2) The authors provide results from several patients with 95% confidence intervals (CIs) that straddle the divide between normal and abnormal when 4 sections are counted, but whose 95% CIs narrow dramatically and fall clearly into normal or abnormal when 10 sections are counted (figure 2 of their article). These data suggest that improved accuracy results when using CIs to determine the appropriate number of sections to be analyzed, but in the examples provided, the average of 4 samples would still have yielded the correct diagnosis. It is nevertheless reasonable to assume that narrower CIs have a greater likelihood of identifying the correct diagnosis.
    Neurology 10/2012; · 8.25 Impact Factor
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    ABSTRACT: OBJECTIVE To repeat the Clinical vs Neurophysiology (Cl vs N Phys) trial using "unequivocally abnormal" signs and symptoms (Trial 2) compared with the earlier trial (Trial 1), which used "usual" signs and symptoms. DESIGN Standard and referenced nerve conduction abnormalities were used in both Trials 1 and 2 as the standard criterion indicative of diabetic sensorimotor polyneuropathy. Physician proficiency (accuracy among evaluators) was compared between Trials 1 and 2. SETTING Academic medical centers in Canada, Denmark, England, and the United States. PARTICIPANTS Thirteen expert neuromuscular physicians. One expert was replaced in Trial 2. RESULTS The marked overreporting, especially of signs, in Trial 1 was avoided in Trial 2. Reproducibility of diagnosis between days 1 and 2 was significantly (P = .005) better in Trial 2. The correlation of the following clinical scores with composite nerve conduction measures spanning the range of normality and abnormality was improved in Trial 2: pinprick sensation (P = .03), decreased reflexes (P = .06), touch-pressure sensation (P = .06), and the sum of symptoms (P = .06). CONCLUSIONS The simple pretrial decision to use unequivocally abnormal signs and symptoms-taking age, sex, and physical variables into account-in making clinical judgments for the diagnosis of diabetic sensorimotor polyneuropathy (Trial 2) improves physician proficiency compared with use of usual elicitation of signs and symptoms (Trial 1); both compare to confirmed nerve conduction abnormality.
    Archives of neurology 09/2012; · 7.58 Impact Factor
  • A Gordon Smith, Robin Marcus
    Journal of diabetes and its complications 07/2012; 26(5):361-2. · 2.11 Impact Factor
  • A Gordon Smith
    Seminars in Neurology 07/2012; 32(3):171-2. · 1.51 Impact Factor
  • J Robinson Singleton, A Gordon Smith
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    ABSTRACT: Diabetes is associated with a variety of chronic and acute neuropathies. In this article, the authors summarize the clinical features of the most common diabetic neuropathies, focusing on those for which therapy is available or under active investigation. Distal symmetric polyneuropathy (DSP) is the most common form. Potential treatments for DSP are discussed in four broad themes: (1) medication and lifestyle therapy to improve hyperglycemia, insulin resistance, and attendant features of metabolic syndrome, including obesity and dyslipidemia; (2) pharmacologic therapy to alter neuropathy natural history aimed at rational targets from known pathophysiology; (3) symptomatic relief of neuropathic pain; and (4) treatment to prevent complications of neuropathy, including stasis ulcers and falls. The approach to the most common acute diabetic neuropathies is also reviewed.
    Seminars in Neurology 07/2012; 32(3):196-203. · 1.51 Impact Factor
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    A Gordon Smith
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    ABSTRACT: Idiopathic neuropathy is one of the most common clinical problems encountered in general medical and neurological practices, accounting for up to 40% of all neuropathies in referral series. Several groups have reported an elevated prevalence of impaired glucose tolerance (IGT) in idiopathic neuropathy subjects, although the only carefully conducted case-control study suggested hypertriglyceridemia was a more important risk factor. The nature of the relationship between IGT and neuropathy is a subject of active debate. An evolving literature suggests metabolic syndrome, particularly dyslipidemia and obesity, are potent neuropathy risk factors for both idiopathic and diabetic neuropathy patients. Once established, diabetic neuropathy is likely to be very difficult to reverse. IGT-associated neuropathy, however, may be more amenable to therapy and could represent an ideal population in which to examine potential therapies for diabetes and obesity related neuropathies. Further research is needed to better define the epidemiological relation between IGT, metabolic syndrome, and neuropathy, its underlying pathophysiology, and to develop appropriate surrogate measures and clinical trials strategies.
    Journal of the Peripheral Nervous System 05/2012; 17 Suppl 2:15-21. · 2.57 Impact Factor
  • A Gordon Smith, J Robinson Singleton
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    ABSTRACT: Diabetes is the most common cause of peripheral neuropathy in the world. More than half of patients with diabetes have neuropathy, and half of patients with neuropathy have diabetes. Diabetic neuropathy is a major cause of disability and health care expense. This article reviews the various forms of diabetic neuropathy with a focus on diagnosis and treatment. Diabetes causes a wide variety of peripheral nerve problems. These can be divided into chronic neuropathies, of which distal symmetric polyneuropathy is the most common, and acute neuropathies, such as diabetic amyotrophy. There is growing evidence suggesting that prediabetic levels of hyperglycemia and other consequences of obesity and dyslipidemia contribute to neuropathy risk. Evolving literature suggests that many of the acute diabetic neuropathies are related to inflammatory mechanisms. An important exception is treatment-related neuropathy, previously known as "insulin neuritis". While disease-altering therapy continues to prove elusive, our understanding of basic disease mechanisms is improving, and new diagnostic and research tools will hopefully lead to novel therapies for distal symmetric diabetic polyneuropathy.
    CONTINUUM Lifelong Learning in Neurology 02/2012; 18(1):60-84.
  • A Gordon Smith
    Archives of internal medicine 01/2012; 172(2):132-3. · 11.46 Impact Factor
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    ABSTRACT: The diagnostic reliability of skin biopsy in small fiber neuropathy depends on the availability of normative reference values. We performed a multicenter study to assess the normative values of intraepidermal nerve fiber (IENF) density at distal leg stratified by age deciles. Eight skin biopsy laboratories from Europe, USA, and Asia submitted eligible data. Inclusion criteria of raw data were healthy subjects 18 years or older; known age and gender; 3-mm skin biopsy performed 10-cm above the lateral malleolus; bright-field immunohistochemistry protocol, and quantification of linear IENF density in three 50-µm sections according to published guidelines. Data on height and weight were recorded, and body mass index (BMI) was calculated in subjects with both available data. Normative IENF density reference values were calculated through quantile regression analysis; influence of height, weight, or BMI was determined by regression analyses. IENF densities from 550 participants (285 women, 265 men) were pooled. We found a significant age-dependent decrease of IENF density in both genders (women p < 0.001; men p = 0.002). Height, weight, or BMI did not influence the calculated 5th percentile IENF normative densities in both genders. Our study provides IENF density normative reference values at the distal leg to be used in clinical practice.
    Journal of the Peripheral Nervous System 09/2010; 15(3):202-7. · 2.57 Impact Factor
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    ABSTRACT: The purpose was to test whether physicians can validly and reproducibly diagnose diabetic sensorimotor polyneuropathy (DSPN). Twelve physicians assessed 24 patients with diabetes mellitus (DM) on consecutive days (576 examinations) with physical features and voice disguised. Results were compared to gold standard 75% group diagnosis (dx) and a nerve conduction score (Sigma5 NC nds). Masking of patients was achieved. Reproducibility measured by the kappa coefficient and compared to Sigma5 NC nd varied considerably among physicians: median and ranges: signs 0.8 (0.32-1.0); symptoms 0.79 (0.36-1.0), and diagnoses 0.47 (0.33-0.84), both low and high scores indicating poor performance. There was substantial agreement between 75% group dx and confirmed NC abnormality (abn). As compared to Sigma5 NC, individual physicians' clinical dx was excessively variable and frequently inaccurate. Study physician dx from signs and symptoms were excessively variable, often overestimating DSPN. Specific approaches to improving clinical proficiency should be tested.
    Muscle & Nerve 08/2010; 42(2):157-64. · 2.31 Impact Factor
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    ABSTRACT: To determine whether repetitive and cumulative exposure to low-frequency pulsed electromagnetic fields (PEMF) targeting painful feet can reduce neuropathic pain (NP), influence sleep in symptomatic diabetic peripheral neuropathy (DPN), and influence nerve regeneration. Randomized, double-blind, placebo-controlled parallel study. Sixteen academic and clinical sites in 13 states. Subjects (N=225) with DPN stage II or III were randomly assigned to use identical devices generating PEMF or sham (placebo) 2 h/d to feet for 3 months. Nerve conduction testing was performed serially. Pain reduction scores using a visual analog scale (VAS), the Neuropathy Pain Scale (NPS), and the Patient's Global Impression of Change (PGIC). A subset of subjects underwent serial 3-mm punch skin biopsies from 3 standard lower limb sites for epidermal nerve fiber density (ENFD) quantification. Subjects (N=225) were randomized with a dropout rate of 13.8%. There was a trend toward reductions in DPN symptoms on the PGIC, favoring the PEMF group (44% vs 31%; P=.04). There were no significant differences between PEMF and sham groups in the NP intensity on NPS or VAS. Twenty-seven subjects completed serial biopsies. Twenty-nine percent of PEMF subjects had an increase in distal leg ENFD of at least 0.5 SDs, while none did in the sham group (P=.04). Increases in distal thigh ENFD were significantly correlated with decreases in pain scores. PEMF at this dosimetry was noneffective in reducing NP. However neurobiological effects on ENFD, PGIC and reduced itching scores suggest future studies are indicated with higher dosimetry (3000-5000 G), longer duration of exposure, and larger biopsy cohort.
    Archives of physical medicine and rehabilitation 08/2009; 90(7):1102-9. · 2.18 Impact Factor
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    ABSTRACT: The objective of these 2 studies was to assess the efficacy of FL-41-tinted lenses in the treatment of benign essential blepharospasm (BEB). A randomized crossover study and a randomized crossover case-control study. The first study included 30 subjects with BEB. The second study included 26 subjects with BEB and 26 controls. For the first study, subjects were randomized to wear either FL-41 or gray-tinted lenses for 2 weeks. After a 2-week washout period, the other lens was worn for 2 weeks. Questionnaires were completed at baseline, after the first lens, and after the second lens. In the second study, surface electromyography (EMG) was used to measure blink frequency, duration, and force while subjects read and wore FL-41, rose, or gray-tinted lenses. Questionnaires were used to assess perceptions of light sensitivity and the effect of light sensitivity on activities of daily living (ADL). EMG was used to measure blink frequency, duration, and force. Most participants observed improvement while wearing both FL-41 and gray-tinted lenses. FL-41-tinted lenses provided superior improvement in the areas of reading, fluorescent light sensitivity, overall light sensitivity, blepharospasm frequency, and blepharospasm severity. FL-41 lenses reduced mean blink rate compared with both rose and gray-tinted lenses, and reduced eyelid contraction force compared with rose-tinted lenses. FL-41 lenses provided both subjective and objective benefit to subjects with BEB. Physicians should consider recommending this noninvasive and inexpensive lens tint to patients with BEB. Proprietary or commercial disclosure may be found after the references.
    Ophthalmology 06/2009; 116(5):997-1001. · 5.56 Impact Factor
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    ABSTRACT: 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 05/2009; 39(4):529-35. · 2.31 Impact Factor
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    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.
    Journal of the Peripheral Nervous System 09/2008; 13(3):218-27. · 2.57 Impact Factor
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    ABSTRACT: 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. 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. 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. These findings demonstrate an association between neuropathy and metabolic syndrome features other than hyperglycemia. Lipid abnormalities are particularly prevalent among neuropathy subjects.
    Journal of the Neurological Sciences 08/2008; 273(1-2):25-8. · 2.24 Impact Factor