Diagnosis and Treatment of Myasthenia Gravis

Renato Mantegazza; Paola Cavalcante

Disclosures

Curr Opin Rheumatol. 2019;31(6):623-633. 

In This Article

The Diagnostic Process

Serum autoantibody determination is the most specific diagnostic tool for the disease. Electromyography (EMG) and clinical response to cholinesterase inhibitors are important for diagnosis confirmation, particularly for seronegative patients, who need differential diagnosis to distinguish myasthenia gravis from other neuromuscular transmission disorders (Figure 2).

Figure 2.

Diagnostic algorithm for myasthenia gravis. Abs, antibodies; AChR, acetylcholine receptor; ChE-Inhib, cholinesterase inhibitor; LRP4, low-density lipoprotein receptor-related protein 4; MG, myasthenia gravis; MuSK, muscle-specific tyrosine-kinase; NMJ, neuromuscular junction; RyR, ryanodine receptor; RNS, repetitive nerve stimulation; SF-EMG, single-fiber electromyography; SP, seropositive; SN, seronegative.

Autoantibody Testing as Specific Diagnostic Tool

Determination of anti-AChR antibodies, observed in ~80% of patients,[1] is the first assay to be performed; if negative anti-MuSK antibodies, present in 5–8% of patients,[1] should be searched (Figure 2). Anti-LRP4 antibodies, the more recent diagnostic marker for the disease,[10] should be tested in double AChR/MuSK-negative patients. They are rarely found in anti-AChR or anti-MuSK antibody-positive patients, possibly representing a subgroup of patients more severely affected at onset.[10] Antibodies to LRP4 were occasionally found in amyotrophic lateral sclerosis in patients with neuromuscular transmission defects and a weak response to cholinesterase inhibitors.[19]

The most sensible diagnostic assay for anti-AChR and anti-MuSK antibodies is radioimmunoassay (RIA).[20,21] The introduction of CBAs has significantly increasing the chance to identify autoantibodies to low affinity clustered AChR, MuSK and LRP4, thus improving myasthenia gravis diagnosis,[22,9,10] although commercial kits are not available. A rapid (less than 1 h) and simple immunostick immunosorbent ELISA has been recently developed for qualitative detection of anti-AChR and anti-MuSK antibodies in serum or whole blood, with 99.1% of specificity and 91.1% of sensitivity for antibodies to AChR.[23] Detection of antibodies to titin by ELISA and to ryanodine receptor (RyR) by western blot is suggestive of thymoma but also present in late-onset myasthenia gravis.[1] Recently, by using a combination of CBA and flow cytometry (cytometric CBAs), antibodies to titin, RyR and voltage-gated Kv1 were found in thymoma, in late-onset myasthenia gravis patients, and in myasthenia gravis patients with concomitant myositis and/or myocarditis; the latter patients had a severe generalized form, and anti-striational antibodies suggested an association of myasthenia gravis with myositis and/or myocarditis.[24] In another study, detection of neuronal autoantibody in thymomatous patients using immunohistology and CBA suggested that these antibodies could serve as biomarkers for neuromyotonia or tumour recurrence.[25]

Neuroelectrophysiological Diagnostic Tests

Neuroelectrophysiological tests are confirmatory of myasthenia gravis and are particularly important in seronegative patients for providing evidence of a neuromuscular transmission defect. These tests include repetitive nerve stimulation (RNS) and single-fibre EMG (SF-EMG).[3] In myasthenic patients, a positive RNS at low frequency (2–5 Hz) is decremental at the fourth/fifth response; such a positivity seems to be less evident in patients recently diagnosed (<4 weeks),[26] likewise RNS is frequently abnormal in patients with myasthenia gravis crisis.[27] Optimal stimulation parameters for an accurate ocular myasthenia gravis diagnosis, using repetitive ocular vestibular-evoked myogenic potentials, were recently determined: a robust decrement in the inferior oblique muscles was observed at repetition rates between 20 and 50 Hz, with an optimum at 30 Hz.[28]

SF-EMG, measuring the neuromuscular jitter during voluntary muscle contraction, is the most sensitive test for myasthenia gravis diagnosis; indeed, examination of limb and facial muscles produces positive results in greater than 90% of patients.[29,30] A recent serial stimulated jitter analysis of the orbicularis oculi muscle in juvenile myasthenia gravis patients showed a significant correlation between electrophysiological data and the Myasthenia Gravis Foundation of America (MGFA) score, suggesting that stimulated jitter values are sensitive biomarkers in this disease subgroup.[31]

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