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

Amyotrophic lateral sclerosis (ALS) remains an ultimately fatal neurodegenerative disease without effective therapy. While recent trials have failed to demonstrate benefit of a variety of therapeutic interventions, including celecoxib, topiramate, creatine (Cudkowicz et al., 2003; Shefner et al., 2004; Cudkowicz et al., 2006), advances in basic science are leading to a proliferation of new agents that will require clinical evaluation. A significant problem in clinical trial design is that large numbers of patients must be studied for long time periods for modest therapeutic benefit to be appreciated, making the design of phase II proof-of-concept trials challenging. For example, the study of topiramate in ALS required 288 patients to be studied over a one-year period in order to obtain a 80% power to detect a slowing of disease progression of 35% (Cudkowicz et al., 2003). The need for large sample size and long study duration is, in part, related to the nature of ALS itself. First, the progression of the disease is variable: some people deteriorate rapidly whereas others have a protracted course (Brooks et al., 1990). Moreover, the disease is inconsistent in its presentation. It often begins in a restricted fashion, affecting an arm, a leg, or the cranial nerve muscles, before gradually generalizing. Furthermore, some patients have a predominantly upper motor neuron presentation while in others lower motor neuron degeneration predominates. In addition to these biological variables, the outcome measures themselves are limited in their inherent ability to detect change. Many measures have been shown to decline over time in ALS, with some having quite linear characteristics (Bryan et al., 2003). However, slow rates of decline combined with variability of measurement makes small changes in disease status very difficult to detect. A measure that is highly sensitive to change and reproducible would therefore be of intense interest and substantial benefit. Electrical impedance myography (EIM) is a non-invasive, painless, quantitative technique for the assessment of muscle that has the potential to provide such an outcome measure for ALS clinical trials (Aaron and Shiffman, 2000; Shiffman et al., 1999; Rutkove et al., 2002). Similar to other bioimpedance-based techniques, EIM relies upon the application and surface measurement of high-frequency, low-intensity electrical current. However, EIM is distinctly different since it focuses on measurement of the impedance in relatively restricted regions of muscle (Rutkove et al., 2002), rather than on large areas of the body. In general, bioimpedance-based methods rely on the concept that tissues can be modeled as networks of resistors and capacitors (Schwan, 1957). In the case of EIM, the lipid bilayers of the muscle cell membranes act as the capacitors, the source of the reactance (X) of the network, and the intra- and extracellular fluids act as the resistors, the source of its resistance (R). The major EIM outcome variable is the phase angle, θ, calculated using the relationship θ = arctan (X/R). Measurements are often taken using multiple electrodes spanning the region of interest, in which case the spatially averaged value, θavg, is used as the principal outcome variable. Work thus far has shown that θavg is effective in assessing both localized disorders (e.g., radiculopathy) and generalized diseases (e.g., inflammatory myopathy), lower values almost invariably reflecting more serious disease (Rutkove et al., 2005a; Tarulli et al., 2005). In addition, long-term prospective evaluation of a single ALS patient has demonstrated a major, steady decline in θavg with time, consistent with known disease behavior (Rutkove et al., 2002). Although we are refining the technique and its method of application (Esper et al., 2006), we have continued to enroll ALS patients for testing using the original method, given the prominent phase reductions observed in that initial case. In this paper we report data on 15 ALS patients followed longitudinally for up to 18 months, to determine the potential for EIM as a technique for measuring outcomes in ALS clinical trials. We compare these results to manual muscle testing (MMT) for the same cohort of patients as well as to historical data for maximal voluntary isometric contraction testing (MVICT) and ALS functional rating scale-revised (ALSFRS-R) (Cedarbaum et al., 1999). We also assess whether a simplified approach to data acquisition may be sufficiently robust for clinical trials application.