Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a median survival of three years from symptom onset. Accessible and reliable biomarkers of motor neuron decline are urgently needed to quicken the pace of drug discovery. Fasciculations represent an early pathophysiological hallmark of ALS and can be reliably detected by high-density surface EMG. We set out to quantify fasciculation potentials prospectively over fourteen months, seeking comparisons with established markers of disease progression. Twenty ALS patients and five patients with benign fasciculation syndrome (BFS) underwent up to seven assessments each. At each assessment, we performed the ALS-Functional Rating Scale, sum power score, slow vital capacity, 30-minute high-density surface EMG recordings from biceps and gastrocnemius and the motor unit number index. To quantify fasciculations, we employed SPiQE (Surface Potential Quantification Engine), which is an automated analytical tool to detect and characterise fasciculations from high-density surface EMG. Linear mixed-effect models were employed to account for the pseudoreplication of serial measurements. In our cohort, the ALS-Functional Rating Scale declined at a rate of 0.65 points per month (p<0.0001), 35% slower than average. In total, 410 ALS and 116 BFS recordings were analysed. Compared to BFS patients, baseline biceps fasciculation frequency was ten times greater in strong ALS muscles and 40 times greater in weak ALS muscles. This was coupled with a decline in fasciculation frequency amongst weak ALS muscles of 7.6/min per month (p=0.003), demonstrating the rise and fall of fasciculation frequency in ALS biceps muscles. Gastrocnemius behaved differently, whereby strong ALS muscles had fasciculation frequencies five times greater than BFS while weak muscles were increased by only 1.5 times. Gastrocnemius demonstrated a significant decline in fasciculation frequency in strong muscles (2.4/min per month, p<0.0001), which leveled off in weak muscles. Fasciculation amplitude, an easily quantifiable surrogate of the reinnervation process, was highest in the biceps muscles that transitioned from strong to weak during the study. Pooled analysis of over 900,000 fasciculations revealed inter-fasciculation intervals <100ms in the biceps of ALS patients, particularly in strong muscles, consistent with the occurrence of doublets. We hereby present the most comprehensive longitudinal quantification of fasciculation parameters in ALS and BFS patients, proposing a unifying model of the interactions between motor unit loss, muscle power and fasciculation frequency. The latter showed promise as a disease biomarker with linear rates of decline in strong gastrocnemius and weak biceps muscles, reflecting the motor unit loss that drives clinical progression.
|Accepted/In press - 13 Jan 2020
- Amyotrophic lateral sclerosis
- Nerve excitability