143 research outputs found
Critical appraisal of the use of alpha lipoic acid (thioctic acid) in the treatment of symptomatic diabetic polyneuropathy
Courtney E McIlduff, Seward B RutkoveDepartment of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USABackground: The most common of the neuropathies associated with diabetes mellitus, diabetic sensorimotor polyneuropathy (DSPN) is a syndrome of diffuse, length-dependent, symmetric nerve dysfunction. The condition is linked with substantial morbidity, frequent healthcare utilization, and compromised quality of life due to related discomfort. Correspondingly, antidepressants, anticonvulsants, and opioids are regularly prescribed with the goal of pain control. However, the agents rarely provide complete pain relief and fail to address progression of the disorder. Whereas strict blood glucose control can slow the onset and worsening of DSPN, near-normoglycemia is not easily attainable. Evidence implicating oxidative processes in the pathogenesis of DSPN offers one potentially important therapeutic avenue. Due to its properties as a potent antioxidant, alpha lipoic acid (ALA) could mitigate the development of DSPN and attenuate resultant symptoms and signs. Approved for treatment of DSPN in Germany, the agent is not more widely used due to uncertainty about its efficacy and reported adverse effects. Here we review the effectiveness and tolerability of ALA in the treatment of symptomatic DSPN.Methods: The MEDLINE, EMBASE, and Cochrane Library databases were searched for English-language literature on the topic. Randomized, blinded studies comparing parenteral and oral ALA with placebo in the treatment of peripheral neuropathy in diabetic adults were selected. Analysis included studies with a level of evidence of at least 2b.Results: The current appraisal summarizes data from 1160 participants in the ALADIN, SYDNEY, ORPIL, SYDNEY 2, and ALADIN III trials. In four of the studies, ALA provided significant improvement in manifestations of DSPN.Conclusion: Treatment with ALA 600 mg iv daily for 3 weeks represents a well-tolerated and effective therapy for DSPN. An oral dose of 600 mg daily administered for up to 5 weeks could offer benefits in symptoms and signs of DSPN without significant side effects.Keywords: alpha lipoic acid, antioxidant, diabetes mellitus, neuropathy, thioctic aci
Electrophysiologic Biomarkers for Assessing Disease Progression and the Effect of Riluzole in SOD1 G93A ALS Mice
Objective: To compare electrical impedance myography (EIM) 50 kHz phase to weight, motor score, paw grip endurance (PGE), CMAP amplitude, and MUNE for the identification of disease progression and the effect of riluzole in the SOD1 G93A mouse. Methods: Twenty-three animals received 8 mg/kg/day riluzole in the drinking water starting at 6 weeks of age; 22 animals served as controls. Weight, motor score, PGE, CMAP, MUNE, and EIM were performed weekly to evaluate disease progression. Results: No difference in clinical disease onset or survival was found between treated and untreated groups. In addition, all methods failed to identify any beneficial effect of riluzole. Thus, data from all animals were combined for additional analyses. Of the 4 parameters, EIM phase showed the earliest change from baseline and the most linear decline throughout the entire measurement period. In addition, EIM phase correlated with PGE, CMAP amplitude, and MUNE (Spearman r = 0.92, 0.90, and 0.72, respectively, p<0.01 for all). The rate of EIM phase decline also correlated with individual animal survival (Spearman r = −0.31, p<0.05). Conclusions: At this dose, riluzole is ineffective in slowing progression of ALS. However, EIM phase shows early linear declines, supporting its potential as a useful new biomarker for preclinical drug testing
Cold Exposure Exacerbates the Development of Diabetic Polyneuropathy in the Rat
Diabetic polyneuropathy (DPN) and cold-induced nerve injury share several pathogenic mechanisms. This study explores whether cold exposure contributes to the development of DPN. Streptozotocin-induced diabetic rats and controls were exposed to a room temperature (23°C) or cold environment (10°C). H-reflex, tail and sciatic motor, and sensory nerve conduction studies were performed. Analyses of sural nerve, intraepidermal nerve fibers, and skin and nerve nitrotyrosine ELISAs were performed. Diabetic animals exposed to a cold environment had an increased H-reflex four weeks earlier than diabetic room temperature animals (P = .03). Cold-exposed diabetic animals also had greater reduction in motor conduction velocities at 20 weeks (P = .017), decreased skin nerve fiber density (P = .037), and increased skin nitrotyrosine levels (P = .047). Cold exposure appears to hasten the development of DPN in the rat STZ model of diabetes. These findings support that further study into the relationship between ambient temperature and DPN is warranted
Optimizing Electrode Configuration for Electrical Impedance Measurements of Muscle via the Finite Element Method
Electrical impedance myography (EIM) is a technique for the evaluation of neuromuscular diseases, including amyotrophic lateral sclerosis and muscular dystrophy. In this study, we evaluated how alterations in the size and conductivity of muscle and thickness of subcutaneous fat impact the EIM data, with the aim of identifying an optimized electrode configuration for EIM measurements. Finite element models were developed for the human upper arm based on anatomic data; material properties of the tissues were obtained from rat and published sources. The developed model matched the frequency-dependent character of the data. Of the three major EIM parameters, resistance, reactance, and phase, the reactance was least susceptible to alterations in the subcutaneous fat thickness, regardless of electrode arrangement. For example, a quadrupling of fat thickness resulted in a 375% increase in resistance at 35 kHz but only a 29% reduction in reactance. By further optimizing the electrode configuration, the change in reactance could be reduced to just 0.25%. For a fixed 30 mm distance between the sense electrodes centered between the excitation electrodes, an 80 mm distance between the excitation electrodes was found to provide the best balance, with a less than 1% change in reactance despite a doubling of subcutaneous fat thickness or halving of muscle size. These analyses describe a basic approach for further electrode configuration optimization for EIM
A Technique for Performing Electrical Impedance Myography in the Mouse Hind Limb: Data in Normal and ALS SOD1 G93A Animals
Objective: To test a method for performing electrical impedance myography (EIM) in the mouse hind limb for the assessment of disease status in neuromuscular disease models. Methods: An impedance measuring device consisting of a frame with electrodes embedded within an acrylic head was developed. The head was rotatable such that data longitudinal and transverse to the major muscle fiber direction could be obtained. EIM measurements were made with this device on 16 healthy mice and 14 amyotrophic lateral sclerosis (ALS) animals. Repeatability was assessed in both groups. Results: The technique was easy to perform and provided good repeatability in both healthy and ALS animals, with intra-session repeatability (mean ± SEM) of 5% ±1% and 12% ±2%, respectively. Significant differences between healthy and ALS animals were also identified (e.g., longitudinal mean 50 kHz phase was 18±0.6° for the healthy animals and 14±1.0° for the ALS animals, p = 0.0025). Conclusions: With this simple device, the EIM data obtained is highly repeatable and can differentiate healthy from ALS animals. Significance: EIM can now be applied to mouse models of neuromuscular disease to assess disease status and the effects of therapy
ALS Longitudinal Studies With Frequent Data Collection at Home: Study Design and Baseline Data
Objective: To design an ALS clinical study in which patients are remotely recruited, screened, enrolled and then assessed via daily data collection at home by themselves or caregivers. Methods: This observational, natural-history study included two academic medical centers, one providing overall clinical management and the other overseeing computing and web-services design and management. Both healthy and ALS subjects were recruited on the Internet via advertisement on governmental and foundation websites as well as through Facebook and Google paid advertisements. Individuals underwent screening and enrollment remotely, including signing an electronic informed consent form. Participants were then provided self-measurement equipment and instructed on their use through a series of web-based videos. The equipment included a handgrip dynamometer, spirometer with smartphone connection, electrical impedance myography device, and an activity tracker. ALS Functional Rating Scale-Revised data were also collected. Subjects were asked to collect data daily for three months and twice-weekly for the subsequent six months. Results: One hundred and eleven ALS patients and 30 healthy individuals enrolled in the study from across 41 states (74 men, 62 women). Baseline median ALSFRS-R score was 33. Seventy two percent of the ALS patients sent equipment and 88% of the healthy subjects sent equipment were able to complete a first set of measurements. Expected baseline differences between the ALS patients and healthy participants were identified for all measures. Conclusions: It is possible to design and institute an at-home based study in ALS patients, using a number of state-of-the-art approaches, including web-based consenting and training and Internet-connected measurement devices
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A Comparison of Three Electrophysiological Methods for the Assessment of Disease Status in a Mild Spinal Muscular Atrophy Mouse Model
Objectives: There is a need for better, noninvasive quantitative biomarkers for assessing the rate of progression and possible response to therapy in spinal muscular atrophy (SMA). In this study, we compared three electrophysiological measures: compound muscle action potential (CMAP) amplitude, motor unit number estimate (MUNE), and electrical impedance myography (EIM) 50 kHz phase values in a mild mouse model of spinal muscular atrophy, the Smn1c/c mouse. Methods: Smn1c/c mice (N = 11) and wild type (WT) animals (−/−, N = 13) were measured on average triweekly until approximately 1 year of age. Measurements included CMAP, EIM, and MUNE of the gastrocnemius muscle as well as weight and front paw grip strength. At the time of sacrifice at one year, additional analyses were performed on the animals including serum survival motor neuron (SMN) protein levels and muscle fiber size. Results: Both EIM 50 kHz phase and CMAP showed strong differences between WT and SMA animals (repeated measures 2-way ANOVA, P<0.0001 for both) whereas MUNE did not. Both body weight and EIM showed differences in the trajectory over time (p<0.001 and p = 0.005, respectively). At the time of sacrifice at one year, EIM values correlated to motor neuron counts in the spinal cord and SMN levels across both groups of animals (r = 0.41, p = 0.047 and r = 0.57, p = 0.003, respectively), while CMAP did not. Motor neuron number in Smn1c/c mice was not significantly reduced compared to WT animals. Conclusions: EIM appears sensitive to muscle status in this mild animal model of SMA. The lack of a reduction in MUNE or motor neuron number but reduced EIM and CMAP values support that much of the pathology in these animals is distal to the cell body, likely at the neuromuscular junction or the muscle itself
Hindlimb suspension in Wistar rats: Sex-based differences in muscle response
Ground-based animal models have been used extensively to understand the effects of microgravity on various physiological systems. Among them, hindlimb suspension (HLS), developed in 1979 in rats, remains the gold-standard and allows researchers to study the consequences of total unloading of the hind limbs while inducing a cephalic fluid shift. While this model has already brought valuable insights to space biology, few studies have directly compared functional decrements in the muscles of males and females during HLS. We exposed 28 adult Wistar rats (14 males and 14 females) to 14 days of HLS or normal loading (NL) to better assess how sex impacts disuse-induced muscle deconditioning. Females better maintained muscle function during HLS than males, as shown by a more moderate reduction in grip strength at 7 days (males: −37.5 ± 3.1%, females: −22.4 ± 6.5%, compared to baseline), that remains stable during the second week of unloading (males: −53.3 ± 5.7%, females: −22.4 ± 5.5%, compared to day 0) while the males exhibit a steady decrease over time (effect of sex × loading p = 0.0002, effect of sex × time × loading p = 0.0099). This was further supported by analyzing the force production in response to a tetanic stimulus. Further functional analyses using force production were also shown to correspond to sex differences in relative loss of muscle mass and CSA. Moreover, our functional data were supported by histomorphometric analyzes, and we highlighted differences in relative muscle loss and CSA. Specifically, female rats seem to experience a lesser muscle deconditioning during disuse than males thus emphasizing the need for more studies that will assess male and female animals concomitantly to develop tailored, effective countermeasures for all astronauts
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Electrical Characteristics of Rat Skeletal Muscle in Immaturity, Adulthood and After Sciatic Nerve Injury, and Their Relation to Muscle Fiber Size
Localized impedance methods can provide useful approaches for assessing neuromuscular disease. The mechanism of these impedance changes remains, however, uncertain. In order to begin to understand the relation of muscle pathology to surface impedance values, 8 immature rats, 12 mature rats, and 8 mature rats that had undergone sciatic crush were killed. Tissue from the gastrocnemius muscle from each animal was measured in an impedance cell, and the conductivity and relative permittivity of the tissue calculated in both the longitudinal and transverse directions for frequencies of 2 kHz to 1 MHz. In addition, quantitative histological analysis was performed on the tissue. Significant elevations in transverse conductivity and transverse relative permittivity were found with animal growth, but longitudinal values showed no difference. After sciatic crush, both transverse and longitudinal conductivity increased significantly, with no change in the relative permittivity in either direction. The frequency dependence of the values also changed after nerve injury. In the healthy animals, there was a strong linear relation between measured conductivity and relative permittivity with cell area, but not for the sciatic crush animals. These results provide a first step toward developing a comprehensive understanding of how the electrical properties of muscle alter in neuromuscular disease states
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Utilizing a handheld electrode array for localized muscle impedance measurements
Introduction: Electrical impedance myography (EIM) is a non-invasive technique used for assessment of muscle health in which a high-frequency, low-amplitude electric current is applied to the skin overlying a muscle, and the resulting surface voltage is measured. We have previously used adhesive electrodes, application of which is inconvenient. We present data using a handheld electrode array (HEA) that we devised to expedite the EIM procedure in a clinical setting. Methods: Thirty-four healthy volunteers and 24 radiculopathy subjects underwent EIM testing using the HEA and adhesive electrodes. Results: The HEA was shown to have good test-retest reproducibility, with intraclass correlation coefficients as high as 0.99. HEA data correlated strongly with data from adhesive electrodes, ρ = 0.85 in healthy volunteers (p < 0.001) and ρ = 0.75 in radiculopathy subjects (p < 0.001). Discussion: These data support the potential use of a handheld array for performing rapid localized surface impedance measurements
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