A Gordon Smith

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

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Publications (48)215.87 Total impact

  • J. Robinson Singleton · A. Gordon Smith · Robin L. Marcus
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    ABSTRACT: Length-dependent neuropathy is the most common and costly complication of diabetes and frequently causes injury primarily to small-diameter cutaneous nociceptive fibers. Not only persistent hyperglycemia but also metabolic, endocrine, and inflammatory effects of obesity and dyslipidemia appear to play an important role in the development of diabetic neuropathy. Rational therapies aimed at direct control of glucose or its increased entry into the polyol pathway, oxidative or nitrosative stress, advanced glycation end product formation or signaling, microvascular ischemia, or adipocyte-derived toxicity have each failed in human trials of diabetic neuropathy. Aerobic exercise produces salutary effects in many of these pathogenic pathways simultaneously and, in both animal models and human trials, has been shown to improve symptoms of neuropathy and promote re-growth of cutaneous small-diameter fibers. Behavioral reduction in periods of seated, awake inactivity produces multimodal metabolic benefits similar to exercise, and the two strategies when combined may offer sustained benefit to peripheral nerve function.
    No preview · Article · Dec 2015 · Current Diabetes Reports
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    ABSTRACT: Background We used in vivo corneal confocal microscopy to investigate structural differences in the sub-basal corneal nerve plexus in chronic migraine patients and a normal population. We used a validated questionnaire and tests of lacrimal function to determine the prevalence of dry eye in the same group of chronic migraine patients. Activation of the trigeminal system is involved in migraine. Corneal nociceptive sensation is mediated by trigeminal axons that synapse in the gasserian ganglion and the brainstem, and serve nociceptive, protective, and trophic functions. Noninvasive imaging of the corneal sub-basal nerve plexus is possible with in vivo corneal confocal microscopy.Methods For this case–control study, we recruited chronic migraine patients and compared them with a sex- and age-similar group of control subjects. Patients with peripheral neuropathy, a disease known to be associated with a peripheral neuropathy, or prior corneal or intraocular surgery were excluded. Participants underwent in vivo corneal confocal microscopy using a Heidelberg Retinal Tomography III confocal microscope with a Rostock Cornea Module. Nerve fiber length, nerve branch density, nerve fiber density, and tortuosity coefficient were measured using established methodologies. Migraine participants underwent testing of basal tear production with proparacaine, corneal sensitivity assessment with a cotton-tip applicator, measurement of tear break-up time, and completion of a validated dry eye questionnaire.ResultsA total of 19 chronic migraine patients and 30 control participants completed the study. There were no significant differences in age or sex. Nerve fiber density was significantly lower in migraine patients compared with controls (48.4 ± 23.5 vs 71.0 ± 15.0 fibers/mm2, P < .001). Nerve fiber length was decreased in the chronic migraine group compared with the control group, but this difference was not statistically significant (21.5 ± 11.8 vs 26.8 ± 5.9 mm/mm2, P < .084). Nerve branch density was similar in the two groups (114.0 ± 92.4 vs 118.1 ± 55.9 branches/mm2, P < .864). Tortuosity coefficient and log tortuosity coefficient also were similar in the chronic migraine and control groups. All migraine subjects had symptoms consistent with a diagnosis of dry eye syndrome.Conclusions We found that in the sample used in this study, the presence of structural changes in nociceptive corneal axons lends further support to the hypothesis that the trigeminal system plays a critical role in the pathogenesis of migraine. In vivo corneal confocal microscopy holds promise as a biomarker for future migraine research as well as for studies examining alterations of corneal innervation. Dry eye symptoms appear to be extremely prevalent in this population. The interrelationships between migraine, corneal nerve architecture, and dry eye will be the subject of future investigations.
    No preview · Article · Apr 2015 · Headache The Journal of Head and Face Pain
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    ABSTRACT: Objective: Unmyelinated cutaneous axons are vulnerable to physical and metabolic injury, but also capable of rapid regeneration. This balance may help determine risk for peripheral neuropathy associated with diabetes or metabolic syndrome. Capsaicin application for 48 hours induces cutaneous fibers to die back into the dermis. Regrowth can be monitored by serial skin biopsies to determine intraepidermal nerve fiber density (IENFD). We used this capsaicin axotomy technique to examine the effects of exercise on cutaneous regenerative capacity in the setting of metabolic syndrome. Methods: Baseline ankle IENFD and 30-day cutaneous regeneration after thigh capsaicin axotomy were compared for participants with type 2 diabetes (n = 35) or metabolic syndrome (n = 32) without symptoms or examination evidence of neuropathy. Thirty-six participants (17 with metabolic syndrome) then joined twice weekly observed exercise and lifestyle counseling. Axotomy regeneration was repeated in month 4 during this intervention. Results: Baseline distal leg IENFD was significantly reduced for both metabolic syndrome and diabetic groups. With exercise, participants significantly improved exercise capacity and lower extremity power. Following exercise, 30-day reinnervation rate improved (0.051 ± 0.027 fibers/mm/day before vs 0.072 ± 0.030 after exercise, p = 0.002). Those who achieved improvement in more metabolic syndrome features experienced a greater degree of 30-day reinnervation (p < 0.012). Interpretation: Metabolic syndrome was associated with reduced baseline IENFD and cutaneous regeneration capacity comparable to that seen in diabetes. Exercise-induced improvement in metabolic syndrome features increased cutaneous regenerative capacity. The results underscore the potential benefit to peripheral nerve function of a behavioral modification approach to metabolic improvement.
    No preview · Article · Jan 2015 · Annals of Neurology
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    Melissa Cortez · J Robinson Singleton · A Gordon Smith
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    ABSTRACT: There is increasing evidence that impaired glucose tolerance (IGT) or metabolic syndrome may result in peripheral nerve injury, although the exact relationship between the conditions is still being characterized. There is animal model, epidemiologic, and clinical evidence to suggest a pathophysiologic relationship between neuropathy and metabolic syndrome, along with its components including obesity, dyslipidemia, and insulin resistance. IGT and metabolic syndrome are associated with subclinical nerve damage or are typically painful and sensory predominant, although autonomic involvement may also occur. Because there is often preferential small fiber injury and nerve conduction studies may be relatively insensitive, skin biopsy with assessment of intraepidermal nerve fiber density is often used to confirm the diagnosis. Treatment of metabolic syndrome and IGT-associated neuropathies should include diet and exercise counseling, maintenance of normoglycemia, and targeted pharmacologic therapy for modifiable risk factors. Further research is required to fully elucidate the complex pathophysiology, as well as identify optimal diagnostic and treatment approaches.
    Full-text · Article · Nov 2014 · Handbook of Clinical Neurology
  • A Gordon Smith · Ted M Burns

    No preview · Article · Nov 2014 · Neurology
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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.
    Preview · Article · Oct 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.
    No preview · Article · Jul 2014 · Journal of diabetes and its complications
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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.
    No preview · Article · Aug 2013 · Cornea
  • 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.
    No preview · Article · May 2013 · Journal of diabetes and its complications
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    ABSTRACT: Unlabelled: 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.
    Full-text · Article · May 2013 · The journal of pain: official journal of the American Pain Society
  • 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.
    No preview · Article · Oct 2012 · Neurology
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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.
    Full-text · Article · Sep 2012 · Archives of neurology
  • A Gordon Smith · Robin Marcus

    No preview · Article · Jul 2012 · Journal of diabetes and its complications
  • A Gordon Smith

    No preview · Article · Jul 2012 · Seminars in Neurology
  • 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.
    No preview · Article · Jul 2012 · Seminars in Neurology
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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.
    Preview · Article · May 2012 · Journal of the Peripheral Nervous System
  • 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.
    No preview · Article · Feb 2012 · CONTINUUM Lifelong Learning in Neurology
  • A Gordon Smith

    No preview · Article · Jan 2012 · Archives of internal medicine
  • A. Gordon Smith

    No preview · Article · Jan 2012 · Archives of Internal Medicine
  • Mengjing Huan · A. Gordon Smith
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    ABSTRACT: Acute weakness is a common neurological emergency. One of the most frequent neuromuscular causes of acute weakness is Guillain–Barré ­syndrome (GBS). This chapter reviews the epidemiology, pathogenesis, differential diagnosis, clinical presentation, and variants of GBS. Treatment options are discussed including an evidence-based review of various immunomodulatory therapies and practical, symptomatic management. Finally, the chapter covers prognosis and differentiation between acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). This chapter aims to improve understanding and therefore diagnosis and management of a classic neuromuscular disease.
    No preview · Chapter · Jan 2012