Electrical impedance myography to assess outcome in amyotrophic lateral sclerosis clinical trials

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Clinical Neurophysiology (Impact Factor: 3.1). 12/2007; 118(11):2413-8. DOI: 10.1016/j.clinph.2007.08.004
Source: PubMed


Standard outcome measures used for amyotrophic lateral sclerosis (ALS) clinical trials, including the ALS functional rating scale-revised (ALSFRS-R), maximal voluntary isometric contraction testing (MVICT), and manual muscle testing (MMT), are limited in their ability to detect subtle disease progression. Electrical impedance myography (EIM) is a new non-invasive technique that provides quantitative data on muscle health by measuring localized tissue impedance. This study investigates whether EIM could provide a new outcome measure for use in ALS clinical trials work.
Fifteen ALS patients underwent repeated EIM measurements of one or more muscles over a period of up to 18 months and the primary outcome variable, theta(z-max), measured. The theta(z-max) megascore was then calculated using the same approach as has been applied in the past for MVICT. This and the MMT data were then used to assess each measure's statistical power to detect a given effect on disease progression in a hypothetical planned clinical therapeutic trial.
theta(z-max) showed a mean decline of about 21% for the test period, averaged across all patients and all tested muscles. The theta(z-max) megascore had a power of 73% to detect a 10% treatment effect in our planned hypothetical trial, as compared to a 28% power for MMT. These results also compared favorably to historical data for ALSFRS-R and MVICT arm megascore from the trial of celecoxib in ALS, where both measures had only a 23% power to detect the same 10% treatment effect.
The theta(z-max) megascore may provide a powerful new outcome measure for ALS clinical trials.
The application of EIM to future ALS trials may allow for smaller, faster studies with an improved ability to detect subtle progression of the disease and treatment effects.

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Available from: Ronald Aaron, Jul 21, 2014
    • "Skin biopsies are also used for evaluation of abnormalities in cutaneous nerve fibers, as often mitochondrial damage is seen in the axonal end of nerve fibers (McCarthy et al., 1995). Many accurate methods like electromyography help in muscle examination in patients (Rutkove et al., 2007). Blood biomarkers can also be used for diagnosis of ALS, these include markers related to the oxidative stress (e.g. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neural disorder that causes death of the motor neurons in the brain and spinal cord; this affects the voluntary muscles and gradually leads to paralysis of the whole body. Most ALS cases are sporadic, though about 5-10% are familial.ALS is caused by multiple factors including mutation in any one of a number of specific genes, one of the most frequently affected is superoxide dismutase (SOD) 1. Alterations in SOD 1 have been linked with several variants of familial ALS. SOD 1 is a powerful antioxidant enzyme that protects cells from the damaging effects of superoxide radicals. The enzyme binds both copper and zinc ions that are directly involved in the deactivation of toxic superoxide radicals. Mutated SOD1 gene can acquire both gain and loss of function mutations. The most commonly identified mutations in SOD1 that affect protein activity are D90A, A4V and G93A. Deleterious mutations have been shown to modify SOD1 activity, which leads to the accumulation of highly toxic hydroxyl radicals. Accumulation of these free radicals causes degradation of both nuclear and mitochondrial DNA and protein misfolding, features which can be used as pathological indicators associated with ALS. Numerous clinical trials have been carried out over last few years with limited success. No definite treatment option is available and currently ALS is partially managed by drugs and other supportive therapies. In some patients advanced techniques like gene and stem cell therapy have been trialed. However no definitive treatment option can provide a cure, consequently there is a need to identify new approaches for treatment of this ultimately fatal disease.
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    • "However, these methods fail to reliably monitor disease progression and hence effects of treatment. More advanced techniques, such as motor unit number index, Bayesian MUNE, and electrical impedance myography, are more accurate but still need further validation against neuropathological correlates [23–25]. As far as upper motor neuron involvement is concerned, transcranial magnetic stimulation (TMS) and its variants are useful tools to evaluate motor cortical and corticospinal dysfunction and discriminate between ALS and mimic disorders. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal condition primarily characterized by the selective loss of upper and lower motor neurons. At present, the diagnosis and monitoring of ALS is based on clinical examination, electrophysiological findings, medical history, and exclusion of confounding disorders. There is therefore an undeniable need for molecular biomarkers that could give reliable information on the onset and progression of ALS in clinical practice and therapeutic trials. From a practical point of view, blood offers a series of advantages, including easy handling and multiple testing at a low cost, that make it an ideal source of biomarkers. In this review, we revisited the findings of many studies that investigated the presence of systemic changes at the molecular and cellular level in patients with ALS. The results of these studies reflect the diversity in the pathological mechanisms contributing to disease (e.g., excitotoxicity, oxidative stress, neuroinflammation, metabolic dysfunction, and neurodegeneration, among others) and provide relatively successful evidence of the usefulness of a wide-ranging panel of molecules as potential biomarkers. More studies, hopefully internationally coordinated, would be needed, however, to translate the application of these biomarkers into benefit for patients.
    Full-text · Article · Jun 2014 · BioMed Research International
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    • "From these, the muscle’s electrical characteristics, including its resistance, reactance, and phase are calculated. Studies have shown the potential value of these EIM values as biomarkers for assessing disease status and progression, in amyotrophic lateral sclerosis [2], spinal muscular atrophy [3], and myositis [4]; ongoing work suggests that it could also be potentially useful as a diagnostic tool in helping to differentiate neuromuscular illness [5]. "
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    ABSTRACT: 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. 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. 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). With this simple device, the EIM data obtained is highly repeatable and can differentiate healthy from ALS animals. EIM can now be applied to mouse models of neuromuscular disease to assess disease status and the effects of therapy.
    Preview · Article · Sep 2012 · PLoS ONE
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