Diagnosis of Myasthenia Gravis May Be Challenging

By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: Mimics of myasthenia gravis, including functional neurologic disorder, progressive external ophthalmoplegia, chronic ptosis, oculopharyngeal muscular dystrophy, mitochondrial cytopathy, or low-grade myositis, can make the diagnosis of myasthenia gravis difficult.

SOURCE: Harrison P, Barton J, Winkel A. Chronic mimics of myasthenia gravis: A retrospective case series. Neuromuscul Disord 2023;33:250-256.

Characterized by fluctuating ptosis, diplopia, and bulbar and skeletal muscle weakness, myasthenia gravis (MG) is an autoimmune disorder with a rising prevalence, likely as the result of our aging population, a longer life span, and improved diagnosis. Diagnosis may be challenging but is facilitated by the presence of antibodies (Abs), including acetylcholine receptor Abs (AchR Ab), present in 85%; muscle-specific tyrosine kinase (MuSK) Abs, present in 8%; and low-density lipoprotein receptor-related protein 4 (LRP4) Abs, present in 1%, leaving 6% of patients seronegative. Diagnosis may be challenging, particularly among ocular myasthenia patients, where Ab positivity stands at 50%. Which disorders mimic MG?

All patients at the Neurology Department, Sunshine Coast University Hospital, Birtinya, Queensland, Australia, between 2018 and 2021, given an initial diagnosis of MG but subsequently reclassified following detailed neurophysiologic and clinical study, were reviewed in this retrospective case series analysis using a local neurophysiology database. Inclusion criteria encompassed appropriate clinical findings and any one of the following: positive AchR or MuSK Abs, unequivocally positive response to anticholinesterases, > 10% decrement on repetitive nerve stimulation, or positive single fiber electromyography (SFEMG) study with > 10% captured pairs demonstrating abnormal jitter.

Exclusionary criteria included equivocal neurophysiology findings or those with a prior diagnosis of MG already documented by neurophysiologic testing. SFEMG was performed in standard fashion, after discontinuing anticholinesterase agents prior to examination where possible, and was considered abnormal if more than 2/20 pairs had jitter exceeding the expected reference range. The muscle studied was based on the degree of clinical involvement. Statistical analysis included mean and standard deviation, calculated for age and duration of misdiagnosis, with data normality assessed visually with a histogram.

During the study period, 61 patients underwent SFEMG, referred either for a de novo diagnosis of MG, for confirmatory testing of existing MG but with a refractory or atypical course, or for exclusionary testing of other possibilities. Misdiagnosis of MG was found in eight patients, six who were seronegative and two who were seropositive for AchR Ab. Of these, four were diagnosed as having a functional neurologic disorder, and four were diagnosed with one each of progressive external ophthalmoplegia, chronic ptosis, oculopharyngeal muscular dystrophy, or an undifferentiated disorder with either a mitochondrial cytopathy or low-grade myositis. Seven of eight mimics were female. The average duration of misdiagnosis was nine years, with consequent exposure to unnecessary medications, including anticholinesterase medication (8/8), immunosuppression (3/8), intravenous immunoglobulin or plasmapheresis (one each), and thymectomy (two patients). One functional patient was intubated on three occasions on presentation to the emergency department, despite a lack of objective respiratory failure. Ocular complaints were the most common in mimics (7/8), including ptosis or pseudo-ptosis (4/8), subjective diplopia (2/8), or visual blurring (1/8). Muscular weakness (5/8) and bulbar weakness (2/8) were less common, and 3/8 had respiratory symptoms, all functional patients.

MG mimics should be suspected in patients who are static and refractory to treatment, and functional disease may be suspected in patients with frequent flares. Electrophysiologic testing, particularly SFEMG, is helpful in avoiding over-diagnosis.

COMMENTARY

Diagnosis of ocular myasthenia may be challenging, since symptoms are limited to the eyes and 50% of patients are seronegative. The study compared 53 myasthenic patients, 39 seropositive and 14 seronegative, to 19 healthy and 18 disease controls with either Graves’ orbitopathy, chronic progressive external ophthalmoplegia, or oculopharyngeal muscular dystrophy. Routine ophthalmologic orthoptic measurements, wherein the absolute movement limitation of each eye can be quantified with the synoptophore and deviations between two eyes with the Hess chart, revealed that drift during one minute of persistent gaze on the Hess chart was present only in MG patients. Orthoptic measurement of persistent gaze using a Hess chart may be an alternative, or used in addition, to single fiber electromyography in the diagnosis of ocular myasthenia.¹

REFERENCE

1. Keene KR, de Nie JM, Brink JM, et al. Diagnosing myasthenia gravis using orthoptic measurements: Assessing extraocular muscle fatiguability. J Neurol Neurosurg Psychiatry 2023;94:151.