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Neuromuscular ultrasound as a biomarker in amyotrophic lateral sclerosis

Biomarkers are objective measurements that can serve as indicators of underlying complex biological processes or responses to therapy. The lack of robust biomarkers relevant to degenerative motor neuron diseases hampers efforts to diagnose, treat, and understand the pathophysiology of amyotrophic lateral sclerosis (ALS). Electrodiagnosis by nerve conduction study/electromyography (NCS/EMG) is useful as a diagnostic biomarker for most patients, and the findings are used as a surrogate for spread of disease, which is a key clinical feature of ALS. However, the value of electrodiagnosis as a longitudinal biomarker is limited by its invasive and semiquantitative nature. Also, false positives may occur with polyradiculopathy, and false negatives can occur when early clinical findings are primarily due to upper motor neuron dysfunction. The search for biochemical diagnostic biomarkers is underway, but none are part of routine clinical practice. Biomarkers that can track clinical progression of disease across the diversity of ALS presentations and variable rates of decline would be of immense value, particularly if these reflect prognosis. Electromyography is a poor choice for a longitudinal biomarker because the procedure is painful and the findings are semiquantitative. Several well-tolerated nerve conduction-based electrophysiologic procedures such as motor unit number index and motor unit number estimation may track disease progression but require special training and software, are restricted to the distal muscles, and are sensitive to electrode placement. Electrical impedance myography is a painless method for following ALS progression and can be used on both distal and proximal muscles. Although this is quite promising, the specialized equipment required is not widely available, and the results do not have immediate intuitive meaning. None of these biomarkers are part of standard care models or incorporated into the majority of clinical trials, so rapid, painless, and intuitive biomarkers that reflect longitudinal progression of ALS are still required. Neuromuscular ultrasound (US) has these qualities and is eminently adaptable to any clinical presentation of ALS. In this issue of Muscle & Nerve, Noto and colleagues demonstrate that US can be used as a diagnostic biomarker when trying to distinguish between ALS and multifocal motor neuropathy (MMN), a relevant ALS mimic that is characterized by multifocal nerve enlargement on US. These investigators were able to show that the cross-sectional area (CSA) of the median nerve at the midpoint of the upper arm was significantly smaller in ALS patients than in healthy controls or MMN patients. In individuals with ALS versus MMN, the ratio of the median nerve CSA at the wrist to the upper arm of >1.13 was about 80% sensitive and specific for ALS. These findings confirm that US can assist in distinguishing ALS from MMN and add to the body of evidence showing that ALS is one of the few diseases that demonstrates nerve atrophy. In addition to imaging nerve, US also allows for the efficient and reliable imaging of muscle. Muscles that are easily visualized with US include those of the proximal and distal upper and lower extremities, the diaphragm, and the tongue. Muscle US is very sensitive for the detection of fasciculations and can be used as a diagnostic biomarker to boost the sensitivity of diagnostic criteria for ALS and differentiate between ALS and mimics. These studies indicate that US has a limited role as a diagnostic biomarker for ALS. The combination of a good history and neurologic examination, welldesigned NCS/EMG, and negative neuroimaging is typically adequate for diagnostic purposes, but, in the in the occasional patient with only focal motor clinical and EMG findings, US of median nerve CSA may assist in establishing the diagnosis. Ultrasound identification of widespread fasciculations would also be useful in this scenario as well as in those patients with clinical findings limited to the bulbar musculature. There may also be a role for using US of nerve CSA to distinguish between primary lateral sclerosis and upper motor neuron dominant ALS, which may have implications for clinical trial participation. Correspondence to: J. B. Caress; jcaress@wakehealth.edu