Clinical and Electrophysiologic Responses to Acetylcholinesterase Inhibitors in MuSK-Antibody-Positive Myasthenia Gravis: Evidence for Cholinergic Neuromuscular Hyperactivity

Abstract

Background and PurposePatients with muscle-specific tyrosine kinase (MuSK) antibody (MuSK-Ab)-positive myasthenia gravis (MG) show distinct responses to acetylcholinesterase inhibitors (AChEIs). Although clinical responses to AChEIs in MuSK-Ab MG are reasonably well known, little is known about the electrophysiologic responses to AChEIs. We therefore investigated the clinical and electrophysiologic responses to AChEIs in MuSK-Ab-positive MG patients.MethodsWe retrospectively reviewed the medical records and electrodiagnostic findings of 17 MG patients (10 MuSK-Ab-positive and 7 MuSK-Ab-negative patients) who underwent electrodiagnostic testing before and after a neostigmine test (NT).ResultsThe frequency of intolerance to pyridostigmine bromide (PB) was higher in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (50% vs. 0%, respectively; p=0.044), while the maximum tolerable dose of PB was lower in the former (90 mg/day vs. 480 mg/day, p=0.023). The frequency of positive NT results was significantly lower in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (40% vs. 100%, p=0.035), while the nicotinic side effects of neostigmine were more frequent in the former (80% vs. 14.3%, p=0.015). Repetitive compound muscle action potentials (R-CMAPs) developed more frequently after NT in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (90% vs. 14.3%, p=0.004). The frequency of a high-frequency-stimulation-induced decrement-increment pattern (DIP) was higher in MuSK-Ab-positive patients than in MuSK-Ab-negative patients (100% vs. 17.7%, p=0.003).ConclusionsThese results suggest that MuSK-Ab-positive MG patients exhibit unique and hyperactive responses to AChEIs. Furthermore, R-CMAP and DIP development on a standard AChEI dose may be a distinct neurophysiologic feature indicative of MuSK-Ab-positive MG.

Clinical Significance of Repetitive Compound Muscle Action Potentials in Patients with Myasthenia Gravis: A Predictor for Cholinergic Side Effects of Acetylcholinesterase Inhibitors

“… 9 Furthermore, a small proportion of MG patients show cholinergic hypersensitivity and cannot tolerate even a low dose of AChEIs. 5 In our study, similar to the previous studies, 9 of 71 MG patients did not tolerate oral PB at all, and about one-quarter of 62 MG patients receiving regular treatment with oral PB suffered adverse side effects of PB. In addition, intolerance to PB occurred only in the MG patients with R-CMAPs.…”

“… 7 In addition, R-CMAPs were frequently observed in muscle-specific tyrosine kinase (MuSK)-antibody-positive MG patients during diagnostic neostigmine testing (NT), and a substantial proportion of the MuSK-antibody-positive MG patients with R-CMAPs could not tolerate AChEI at all due to the cholinergic side effects. 5 These findings suggest that the presence of R-CMAPs may predict the side effects and intolerance to oral AChEI by representing the cholinergic activity status in the neuromuscular junction.…”

“…While the intolerance to and the side effects of AChEIs were more frequent in MG patients with R-CMAPs than in those without R-CMAPs, the MGFA postintervention status did not differ significantly between MG patients with and without R-CMAPs, and the response of MG treatment to immunotherapy was good in both groups in the present study. Sometimes AChEIs are poorly tolerated or can lead to clinical worsening in MG patients, especially those who are seropositive for MuSK antibodies, 5 9 10 12 and a cholinergic crisis can occur in severe cases. 13 Nine of the MG patients in our study did not tolerate oral PB.…”

“…R-CMAPs may be induced by AChE inhibitor (AChEI) overdose in patients with MG, and they are rarely seen in MG patients taking a standard dose of AChEI. 5 6 R-CMAPs were found to develop more frequently in MG patients with nicotinic side effects of AChEI than in patients without these side effects. 7 In addition, R-CMAPs were frequently observed in muscle-specific tyrosine kinase (MuSK)-antibody-positive MG patients during diagnostic neostigmine testing (NT), and a substantial proportion of the MuSK-antibody-positive MG patients with R-CMAPs could not tolerate AChEI at all due to the cholinergic side effects.…”

“… 4 These R-CMAPs result from repetitive discharge of muscle fibers after a single stimulation and represent the electrophysiologic status of cholinergic neuromuscular hyperactivity. 4 5 …”