Changes in Motor Unit Number Estimate and Forced Vital Capacity as Predictors of ALS Progression

Background: An independent measure of lower motor neuron function that can be monitored over time is essential to evaluating the effect of drugs or stem cell transplantation and to determining prognosis in amyotrophic lateral sclerosis (ALS). Longitudinal changes in forced vital capacity-percent of predicted (FVC%) and motor unit number estimate (MUNE) may identify patient groups with more rapid disease progression. Objective: We attempted to define cutoff values for 3-month changes in FVC% and MUNE that identify ALS patients with rapidly progressive disease defined as survival of 30 months or less from symptom onset. Design: Cohort study. Subjects: We report data from 26 ALS patients, 10 patients reported previously and 16 patients not reported previously, except for the reproducibility of their MUNE data. Results: Of the 26 patients, 7 had rapid progression. Either a 40% decrease in statistical MUNE or a 20% decrease in FVC% over 3 months identified 6 of 7 rapid progressors (Sensitivity=86% 95% confidence interval [CI] 42.1% - 99.6%). Of the 19 patients without rapid progression, 18 met neither the FVC or MUNE criterion (Specificity = 94.7% CI 95% 74.0% - 99.9%). In a proportional hazards model, 3 month change in both FVC and MUNE were significantly predictive of decreased survival. Conclusion: We suggest the use of a three-month change in MUNE or FVC% as a secondary enrollment criterion in therapeutic trials or to identify a subgroup of rapid progressors that may respond differently to treatments.

Improved motor unit number estimate when motor unit alternation is addressed

Motor unit number estimation (MUNE) is important for determining motoneuron survival with age or in conditions such as amyotrophic lateral sclerosis or spinal cord injury. The original incremental method and approaches that were introduced to minimize alternation (e.g., multiple-point stimulation) are most commonly used, but one must accept the limitation that alternation of motor units may still inflate the estimate. Alternation occurs because axon thresholds are probabilistic and overlap for different axons; therefore, different combination of motor units may respond at a given stimulus intensity. Our aims were to quantify motor unit alternation systematically in the thenar muscles of 35 healthy adults by digital subtraction of EMG and force, and to compare MUNE with and without alternation. Alternation was prevalent, with one to nine occurrences in the first 7 to 11 steps in EMG in 34 of 35 muscles. It occurred in the first 3 steps in EMG in 49% of muscles. This alternation resulted in fewer units than steps in EMG (3 to 10 units at step 7 to 11). Accounting for alternation using digital subtraction reduced MUNE by up to 50%, day-to-day, and between-participant variability in MUNE. These results highlight the need to quantify alternation to improve the reliability and precision of motor unit number estimates, which will allow for detection of smaller changes in motoneuron survival with age, various health conditions, and/or due to an intervention. NEW & NOTEWORTHY Motor unit alternation was quantified systematically for the first time, addressing a major limitation of motor unit number estimates. Accounting for alternation decreased motor unit number estimates, and improved the reliability and precision of the motor unit number estimate, which will allow smaller, clinically relevant changes in motoneuron survival to be detected.

Motor unit number estimate as a predictor of motor dysfunction in an animal model of type 1 diabetes

Peripheral neuropathy is a common complication of diabetes that leads to severe morbidity. In this study, we investigated the sensitivity of motor unit number estimate (MUNE) to detect early motor axon dysfunction in streptozotocin (STZ)-treated mice. We compared the findings with in vitro changes in the morphology and electrophysiology of the neuromuscular junction. Adult Thy1-YFP and Swiss Webster mice were made diabetic following three interdaily intraperitoneal STZ injections. Splay testing and rotarod performance assessed motor activity for 6 wk. Electromyography was carried out in the same time course, and compound muscle action potential (CMAP) amplitude, latency, and MUNE were estimated. Two-electrode voltage clamp was used to calculate quantal content (QC) of evoked transmitter release. We found that an early reduction in MUNE was evident before a detectable decline of motor activity. CMAP amplitude was not altered. MUNE decrease accompanied a drop of end-plate current amplitude and QC. We also observed small axonal loss, sprouting of nerve endings, and fragmentation of acetylcholine receptor clusters at the motor end plate. Our results suggest an early remodeling of motor units through the course of diabetic neuropathy, which can be readily detected by the MUNE technique. The early detection of MUNE anomalies is significant because it suggests that molecular changes associated with pathology and leading to neurodegeneration might already be occurring at this stage. Therefore, trials of interventions to prevent motor axon dysfunction in diabetic neuropathy should be administered at early stages of the disorder.