McArdle sign, a muscle weakness observed with multiple sclerosis, shows evidence of altered neural control


Multiple sclerosis (MS), a common type of demyelinating disease of the central nervous system, is an autoimmune-mediated neurodegenerative disease mainly characterized by inflammatory demyelinating lesions. Multiple sclerosis favors women over men by a ratio of nearly 2 to 1, and it strikes most often between the ages of 20 and 40. Common symptoms of MS include spasticity, fatigue, pain, movement disorders, cognitive impairment, which have a serious impact on the patient’s quality of life and life expectancy. MS can be among the most difficult of all diseases to diagnose because of the puzzling number of symptoms it causes and the multiple ways in which they can present. Magnetic resonance imaging is a very sensitive but disappointingly non-specific technique for visualizing the inflammatory lesions of MS. McArdle’s sign, a rapidly reversible motor weakness brought on by head flexion in individuals with suspected MS, may aid in diagnosis in specific clinical circumstances. It is highly specific and somewhat sensitive for a diagnosis of MS when defined as greater than 10% neck flexion-induced decrease strength using isoinertial finger extension on measurement equipment. Professor Weinshenker at Mayo Clinic was the first to report the potential of utilizing McArdle’s sign in the diagnosis of MS.

There have been reports on typical motor unit (MU) characteristics and the varying effects of interventions on MU characteristics. However, the MU traits and neuromotor control methods related to MS have not been thoroughly defined. Assistant Professor Nathan Schilaty from the University of South Florida along with Filippo Savoldi, Zahra Nasr, and Professor Brian Weinshenker from the Department of Neurology at Mayo Clinic, hypothesized that decomposed electromyography (dEMG) would show larger MUs, higher recruitment thresholds, and lower firing rates for MS patients with the neck in flexion compared to other groups, indicating neural inhibition and mechanically induced neural inhibition. Additionally, they proposed that MS would show variations in these dEMG measurements between neck extension and flexion due to neuromotor inhibition, which results in the muscular weakening seen with McArdle’s sign. Their research is published in the journal Annals of Clinical and Translational Neurology.

The research team showed neuromotor control at the MU level in relation to McArdle’s sign, an MS-specific condition marked by decreased limb strength, commonly measured in finger extensors, with neck flexion relative to extension. Although there were no variations in MU terminal firing rate between MS patients and healthy control or other myelopathies groups, MS patients exhibited higher initial firing rate with the neck in flexion compared to extension. In flexion versus extension, MS patients showed MUs at a greater initial firing rate than healthy control and other myelopathy groups but did not differ in terminal firing rate from the other groups. All dEMG parameters varied between groups, but control from both MS and other myelopathies showed the greatest variation. With the neck extended, the MU common drive showed no variations across groups.

The vast quantity of MUs utilized in a single contraction and the fact that MUs are dynamic during a full contraction make one-dimensional statistics susceptible to producing false positive results. The authors found that while the neck was extended, MS had higher deltaF (deltaF is a paired MU analysis and an indirect technique for estimating synaptic activity due to the magnitude of persistent inward currents) than other groups, but these differences were not present when the neck was flexed. According to this observation, MS patients may be able to increase their motor strength with neck extension with neuromodulation if mechanically caused conduction block is avoided, potentially requiring less central drive than when the neck is flexed.

The authors’ findings showed that isoinertial torque output as evaluated by biomechanical means is strongly predicted by neuromotor control components and their interactions. A cluster analysis of average firing rate, MU amplitude, and deltaF distinguished MS significantly from other groups with three principal components, helping to evaluate the importance of neuromotor control elements better to force output. Intriguingly, the detected clusters showed a marked divergence in Grades 2 and 3 of McArdle’s sign as well as in the % difference of isoinertial torque between neck extension and flexion. The evidence is compelling and points to unique neuromotor control mechanisms and resulting biomechanical alterations in MS. Collectively, the data indicate that MS changes neuromotor control methods (initial firing rate, terminal firing rate, recruitment threshold, MU amplitude, and average firing rate), which in turn contribute to the unique phenomenon known as McArdle’s sign.

In conclusion, the new study by Assistant Professor Nathan Schilaty and colleagues is one of the first to assess neuromotor control features for MS, and it is used in this analysis specifically to assess a distinctive electrophysiologic and clinical occurrence in MS called McArdle’s sign. The authors showed that the neuromotor control methods used by MS patients differ from those used by healthy control and other myelopathy groups. Greater MU amplitude, reduced average firing rate, and increased common drive are significant neural changes between neck extension and flexion that distinguish MS from healthy control and other myelopathy groups and show the neuromechanical integration important to McArdle’s sign phenomenon.


Schilaty ND, Savoldi F, Nasr Z, Weinshenker BG. Neuromotor control associates with muscle weakness observed with McArdle sign of multiple sclerosis. Annals of clinical and translational neurology. 2022 Apr;9(4):515-28.

Go To Annals of clinical and translational neurology.