Electrical impedance myography (EIM) is a new non-invasive technique for the evaluation of neuromuscular disease that relies upon the application and measurement of high-frequency, lowintensity electrical current. EIM assesses disease-induced changes to muscle's normal composition and architecture, including myocyte atrophy and loss, edema, reinnervation, and the deposition of endomysial connective tissue and fat. With application of single-frequency electrical current, EIM can be used to help grade the severity of neuromuscular disease. Assessing electrical impedance across a spectrum of applied frequencies and with current flow at multiple orientations relative to the major muscle fiber direction can provide a more complete picture of muscle condition. EIM holds the promise of serving as an indicator of disease status, thus being useful in clinical trials work and in monitoring effectiveness of treatment in individual patients; ultimately, it may also find diagnostic application. Ongoing efforts have been focused on obtaining a deeper understanding of the basic mechanisms of impedance change, studying EIM in a variety of clinical contexts, and further refining the methods of EIM data acquisition and analysis. KeywordsElectrical impedance; muscle; neuromuscular disease; technique; anisotropy Electrical impedance myography (EIM) is a non-invasive, painless approach to muscle assessment based upon the application and measurement of high-frequency, low-intensity electrical current (Figure 1). In contrast to conventional needle electromyography (EMG) and most standard neurophysiological techniques, EIM does not focus on measuring the inherent electrical activity of the tissues. Rather, similar to diagnostic ultrasound, measurements are made over a small area of interest, with energy being applied to the body and the resultant surface patterns analyzed. Unlike ultrasound, however, in which energy is in the form of sound waves and the main interest is image reconstruction, in the case of EIM, electrical current is used and the output is a set of quantitative parameters describing the state of the muscle, with presently little emphasis on imaging (though this remains possible). Although still in a relatively early stage of development, EIM may have important clinical uses in the future, both as an indicator of neuromuscular disease status and as a diagnostic tool. This review will begin with a brief history of bioelectricity in neuromuscular disease, exploring why electrical impedance measurements have been essentially overlooked as a potential means of muscle assessment. It will then detail the basic concepts underlying impedance measurements in general and the substantial challenges of applying them effectively to muscle.Please address correspondence to: Seward B. Rutkove, MD, Beth Israel Deaconess Medical Center, Department of Neurology, 330 Brookline Avenue, Shapiro 810, Boston, MA 02215; srutkove@bidmc.harvard.edu, Tel: 617-667-8130; Fax: 617-667-8747. NIH Public Access It will then review the data tha...

Advances in stem cell biology have generated intense interest in the prospect of transplanting stem cells into the nervous system for the treatment of neurodegenerative diseases. Here, we report the results of an ongoing phase

Objective Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. Methods A longitudinal, multi-center, prospective natural history study enrolled 26 SMA infants, and 27 control infants less than six months of age. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT Network. Infant motor function scales (TIMPSI, CHOP-INTEND and AIMS) and putative physiologic and molecular biomarkers were assessed prior to 6 months of age and at 6, 9, 12, 18 and 24-months with progression, correlations between motor function and biomarkers and hazard ratios were analyzed. Results Motor function scores (MFS) and CMAP decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95%CI: 6,17). Interpretation These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide “real world”, prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated.

The MITAX, MYOACT and MDI tools, which are now undergoing validity testing, should enhance the consistency, comprehensiveness and reliability of disease activity and damage assessment in patients with myositis.

Sarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7–8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject.

ObjectiveThe US Food and Drug Administration–approved trial, “A Phase 1, Open-Label, First-in-Human, Feasibility and Safety Study of Human Spinal Cord-Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis, Protocol Number: NS2008-1,” is complete. Our overall objective was to assess the safety and feasibility of stem cell transplantation into lumbar and/or cervical spinal cord regions in amyotrophic lateral sclerosis (ALS) subjects.MethodsPreliminary results have been reported on the initial trial cohort of 12 ALS subjects. Here, we describe the safety and functional outcome monitoring results for the final trial cohort, consisting of 6 ALS subjects receiving 5 unilateral cervical intraspinal neural stem cell injections. Three of these subjects previously received 10 total bilateral lumbar injections as part of the earlier trial cohort. All injections utilized a novel spinal-mounted stabilization and injection device to deliver 100,000 neural stem cells per injection, for a dosing range up to 1.5 million cells. Subject assessments included detailed pre- and postsurgical neurological outcome measures.ResultsThe cervical injection procedure was well tolerated and disease progression did not accelerate in any subject, verifying the safety and feasibility of cervical and dual-targeting approaches. Analyses on outcome data revealed preliminary insight into potential windows of stem cell biological activity and identified clinical assessment measures that closely correlate with ALS Functional Rating Scale-Revised scores, a standard assessment for ALS clinical trials.InterpretationThis is the first report of cervical and dual-targeted intraspinal transplantation of neural stem cells in ALS subjects. This approach is feasible and well-tolerated, supporting future trial phases examining therapeutic dosing and efficacy.

Localized bioimpedance analysis is a novel, noninvasive technique with potential application to neuromuscular disease. In this procedure, high-frequency alternating current is passed through muscle, and parameters related to the consequent voltage pattern are evaluated. Currents flowing perpendicular to muscle fibers encounter many more cell membranes than do currents flowing parallel to them, producing surface voltage patterns that are altered by disease. Using this technique, 45 normal subjects and 25 patients with various neuromuscular diseases were studied, including 4 with amyotrophic lateral sclerosis, 4 with inflammatory myopathy, and 11 with inclusion-body myositis. Two parameters, the spatially averaged phase and the effective longitudinal resistivity, were altered in patients with neuromuscular disease. Reductions in phase correlated to disease progression, whereas normalization of phase correlated with disease remission. In patients with inclusion-body myositis, a unique pattern of reduced phase and elevated resistivity was identified. These findings suggest that localized bioimpedance analysis has the potential of playing a substantial role in the diagnostic and therapeutic evaluation of neuromuscular disease.

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