Electrical impedance myography as a biomarker to assess ALS progression

Abstract

Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM’s potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique’s correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.

Clinical Measures of Disease Progression in Amyotrophic Lateral Sclerosis

“…Thus, the method is not truly electrophysiological, in the sense that it is not producing excitation of muscle fibers, but is rather electromorphological. Studies of EIM to date have shown substantial sensitivity to ALS disease status and rate of progression, and high reliability [60][61][62]. Animal work has also strongly supported this concept [63,64].…”

“…For example, patients in a drug study may report less progression than those not on an experimental drug simply because they believe the drug might be working. Indeed, a natural history study evaluating ALSFRS-R along with other measures actually showed the ASLFRS-R to be more sensitive to progression than had been reported in other studies [12], perhaps because there was no subjective bias toward a drug having a therapeutic effect. Another limitation of the ALSFRS-R is that it may be affected by the degree of social support and the presence of depression [13].…”

Assessment of Motor Units in Neuromuscular Disease

“…Electrical impedance myography (EIM) developed by a single laboratory involves a set of electrodes placed over the belly of the muscle [68,69]. A small, high-frequency electrical current is applied and the surface voltage can then be measured.…”

Strength Testing in Motor Neuron Diseases

“…Death in ALS is almost always due to respiratory failure, an aspect of loss of strength not captured in extremity measurements. Second, power analyses comparing sample sizes required to show meaningful effects in different outcome measures have suggested that the ALSFRS-R has the potential to show a statistically significant difference with fewer patients per group than other measures, including quantitative muscle strength and vital capacity [36,38]. These estimates of power are derived primarily from 2 factors: rate of change in the measure over time, and variability across patients.…”