Motor Unit Number Estimation Provides Insight Into Nusinersen Effects in SMA

In recent years, spinal muscular atrophy (SMA) diagnosis and treatment have come a long way. But as more therapies are developed, additional biomarkers for disease progression and response to treatment are increasingly important. A study published in the European Journal of Neurology utilized a new motor unit number estimation (MUNE) method, MScanFit, to assess changes in motor units in adult patients with SMA treated with nusinersen.

Nusinersen, an antisense oligonucleotide, is one of 3 FDA-approved treatments for SMA. It is known to change the course of disease in infants and children, but there are not much data to indicate its effectiveness in adult patients. Motor function decline over time is typical of SMA, so one way to gauge disease progression and treatment efficacy is through electrophysiological markers such as motor unit numbers.

The current study used MScanFit, a new type of MUNE, to compare motor unit organization in adult patients with SMA vs healthy adults and to identify any potential short-term motor unit changes in patients on a regimen of nusinersen. In recent studies, MScanFit was shown to have potential as a biomarker for disease progression. But despite the known motor function effects of SMA, there have not been direct observation or comparisons among patients overall, those on nusinersen, and healthy controls.

The study included a total of 15 adult patients with genetically confirmed, type 3 SMA who were treated with nusinersen at the University Hospital of Cologne in Germany. Ahead of each nusinersen dose, patients’ motor status was clinically assessed with the Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and the 6-minute walk test in those who could walk. Patients with polyneuropathy, diabetes mellitus, neurotoxic medication, any fracture of the nerve being investigated, carpal tunnel syndrome, or herniated cervical intervertebral disc were excluded from the electrophysiological investigation with MScanFit.

Overall, 10 patients were prospectively investigated at study entry and again at a follow-up of between 4 and 8 months later (mean, 4.7 months). All measurements from patients in the study were compared with those from 15 healthy, age-matched controls plus an additional reference group of 10 patients with amyotrophic lateral sclerosis (ALS). Eight patients with SMA used wheelchairs and 7 could walk independently.

MScanFit measurements were taken for each group by stimulating the median nerve of participants’ dominant arms via electrodes placed on the forearms and hands. First, compound muscle action potential (CMAP) scans were done, starting with maximum detectable stimulus response to minimal response. Twenty CMAPs were generated prior to the scan at an automatically set supramaximal level, then the intensity was reduced by regular intervals until there was no longer any motor response. The post scan included 20 CMAPs. The MyScanFit component then went to work within QtracP software to generate models based on the the variance and slope of the recorded CMAP scan.

The CMAP used the same amplitude across groups, and the numbers of motor units in patients recorded were lower in patients with SMA compared with the healthy control group. The number of motor units in ALS, however, were lower than those in SMA.

The clinical testing scores for HFMSE and RULM correlated with the number of motor units measured by MUNE in the study. There were no significant differences in motor neuron numbers between the first study and follow-up scanning overall, but specifically in patients with SMA who could walk, there was a moderate improvement in motor unit numbers and a reduced median amplitude.

The authors conclude that despite the study’s small size, the data indicate that patients who can walk may benefit more from nusinersen than those who cannot walk. As motor units decreased in this group, there was also a mean decrease in amplitude, suggesting that sprouting (a compensating mechanism in chronic motor neuron diseases) does not explain the decrease in amplitude in this instance.

Overall, the study points to MUNE being a valuable tool for monitoring SMA reinnervation and the potential benefits that nusinersen has on regeneration.

“Taken together, our data provide important insights on motor unit loss and re-innervation mechanisms in patients with SMA and depict potential benefits of nusinersen on axonal regeneration,” the authors wrote. The study data also suggest that the MScanFit method is objective and potentially useful for assessing treatment response in SMA.

Reference

Schneider C, Wassermann M, Grether N, et al. Motor unit number estimation in adult patients with spinal muscular atrophy treated with nusinersen. Eur J Neurol. 2021;28(9):3022-3029. doi:10.1111/ene.15005