Clinical Features of MuSK-Positive Myasthenia Gravis

Abstract & Commentary

Source: Evoli A, et al. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain. 2003;126:2304-2311.

Among myasthenia gravis (MG) patients who are seronegative (SNMG) for acetylcholine receptor antibodies (AchR Ab), up to 70% demonstrate positivity for IgG antimuscle-specific kinase (MuSK) antibodies. How do they differ clinically from SNMG patients negative for both AchR Ab and MuSK Ab?

Of 78 SNMG patients with generalized myasthenia, 37 were anti-MuSK positive. Diagnosis of SNMG was based on criteria developed by the MG Foundation of America with repeatedly negative AchR Ab assays and confirmed by a > 11% decrement on repetitive nerve stimulation or increased jitter on single-fiber electromyography. Myopathy and neuropathy were excluded based on normal-needle EMG, nerve conduction studies, and serum creatine kinase in all patients, serum lactate in most, and muscle biopsy in 16. Comparison was made to the remaining 41 MuSK-negative SNMG patients. Students’ t tests and X2 tests with Yates correction provided statistical analysis.

MuSK-positive patients were predominantly female (M/F = 0.3) compared to an even gender distribution in MuSK-negative patients. Mean age of onset was similar in the 2 groups, 35 and 39 years, respectively, but younger patients were more frequently MuSK positive, 56.8% presenting before the age of 40. Acute or subacute onset was more frequent in MuSK-positive myasthenics, most often with ptosis and diplopia rapidly progressing to bulbar weakness. All MuSK-positive patients experienced nasal speech and facial weakness, with 35 of 37 noting dysphagia and ocular difficulties. Respiratory crisis was seen in 17 (46%), but limb weakness was clearly evident in only 12 (32%). Only bulbar weakness (100% vs 58.5%) and respiratory crises (46% vs 7.3%) were significantly more common in MuSK-positive compared to MuSK-negative patients. Repetitive nerve stimulation and edrophonium testing were more often positive in MuSK-negative patients, 78% vs 56.8%, and 82.9% vs 70.3%, respectively. Thymectomy did not appear to benefit MuSK-positive patients, and, despite standard high-dose immunosuppressive therapy, 30% experienced periodic deterioration including respiratory crisis requiring, and responding to, plasma exchange. Many developed permanent facial weakness and dysarthria. MuSK-positive patients were, in most instances, clinically indistinguishable from seropositive MG patients and responded well to anticholinesterase and immunosuppressive medication.

Commentary

Compared to adult MG patients, those with childhood and juvenile-onset MG are more likely to be AchR Ab negative. Do they conversely demonstrate a higher degree of MuSK antibody positivity? Among 40 juvenile MG patients, confirmed by pharmacological testing, 27 underwent repeated AchR Ab testing, and 8 (29%) were consistently negative. All had ptosis and extraocular muscle weakness that worsened with fatigue, and 3 had mild generalized weakness. None were positive for MuSK antibodies.1 Case reports with MuSK positivity in childhood may have correlated with more severe weakness. Previous steroid treatment or thymectomy may also influence positivity. MuSK antibodies appear less frequently in children with ocular or mild generalized disease. — Michael Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, Assistant Editor, Neurology Alert.

Reference

1. Anlar B, Vincent A. Neuropediatrics. 2003;34:110-111.