Nonresponsiveness to anticholinesterase agents in patients with MuSK-antibody-positive MG

Abstract

A significant increase in hyperphosphorylated tau proteins (P-tau) in CSF has been shown in Alzheimer disease (AD), suggesting potential utility as biologic markers of AD. 1 Different subtypes of P-tau proteins perform differently in the discrimination of primary dementia disorders from AD. 2 Recently, we have shown that tau phosphorylated at threonine 231 (P-tau 231P ) correlates with cognitive decline in subjects with mild cognitive impairment (MCI), 3 a group at risk for AD. 4 Here, we examined in an exploratory study whether different P-tau epitopes differ in their accuracy to predict cognitive deterioration within subjects with MCI. Therefore, previously published results on P-tau 231P are again presented briefly for comparison. Moreover, we wished to know whether a combination of different P-tau epitopes is superior to a single P-tau marker for the prediction of cognitive decline.Three P-tau subtypes were measured at baseline in 59 patients with MCI. 4 Clinical follow-up was performed in all patients (mean interval 12.27 months, range 6 to 42 months). The mean (SD) age of the MCI patients (28 female) was 72.56 (7.6) years with a mean Mini-Mental State Examination (MMSE) score of 28.0 (1.9). There were 23 healthy control subjects (HC; 14 female; age 60.0 Ϯ 10.1 years; MMSE 29.2 Ϯ 0.7 points). Study subjects were recruited at two centers (Department of Psychiatry, Ludwig Maximilian University, Munich, Germany, and Department of Clinical Neuroscience, Göteborg, Sweden). P-Tau epitopes including P-tau 231P , tau protein phosphorylated at threonine 181 (P-tau 181P ), and serine 199 (P-tau 199P ) were measured using ELISAs. 2,3 Prediction of annual rate of cognitive decline (measured by MMSE change) was tested for each P-tau epitope in a separate multiple linear regression model. With use of a forward selection method, for each model, age, gender, MMSE at baseline, duration of interval, center, treatment with cognitive enhancers, and the baseline level of the respective P-tau epitope were entered as variables. A variable was entered into the model if the p value

Clinical findings in MuSK‐antibody positive myasthenia gravis: A U.S. experience

“…Unresponsiveness to ACE and actual worsening with standard dosing has been reported previously, 15 and this observation has persisted in later reports. 12,26 Intolerance manifested by severe muscarinic and nicotinic side effects has been observed. 12 As in previous reports, our MuSK-positive patients had a variable response to ACE.…”

“…12,26 Intolerance manifested by severe muscarinic and nicotinic side effects has been observed. 12 As in previous reports, our MuSK-positive patients had a variable response to ACE. 8,15 Nonresponsiveness was observed in 35, hypersensitivity or worsening of symptoms in 10, intolerance from side effects in 15, and no clinical improvement in 20 patients.…”

“…Nonresponsiveness to ACE comprised hypersensitivity or worsening of MG symptoms, intolerance from side effects, or lack of clinical response. 12 MGFA classification was based on overall assessment of symptoms and signs. 13 Patients were also classified by the MGFA postintervention status at their last follow-up.…”

Anti-MuSK autoantibodies block binding of collagen Q to MuSK

“…10,11 MuSK-MG patients respond favorably to immunotherapy, but usually do not respond to, or are even worsened by, cholinesterase inhibitors. [12][13][14][15] Anti-AChR antibodies comprise IgG1 and IgG3 moieties that bind complement whereas anti-MuSK antibodies are largely IgG4 that do not activate complement, and complement deposits at the NMJ are sparse. 16 -18 However, the exact target of MuSK-IgG remains elusive.…”

Muscle‐specific kinase (MuSK) antibody‐associated myasthenia gravis after bone marrow transplantation

“…3,5 Pyridostigmine is often ineffective, but most patients respond favorably to immunosuppressants. 5,6,11 Antibodies to AchR are found in over 20% of BMT patients, but most do not develop MG for unknown reasons. 14 There are only 20 previously reported cases of MG after BMT (Table 1).…”