Myasthenia Gravis Workup: A Comprehensive Diagnostic Overview

Diagnosing myasthenia gravis (MG) requires a thorough evaluation, as its symptoms can mimic other neuromuscular disorders. Early and accurate identification is crucial for initiating appropriate treatment and preventing complications. A structured workup combines clinical assessment with specialized testing to confirm the diagnosis and determine disease severity.

To achieve diagnostic certainty, multiple approaches are utilized, including neurological exams, antibody testing, electrophysiological studies, imaging, and pharmacological assessments. Each method provides valuable insights into different aspects of the disease process.

Clinical Presentation

MG manifests with fluctuating muscle weakness that worsens with exertion and improves with rest, a hallmark feature distinguishing it from other neuromuscular disorders. The condition primarily affects voluntary muscles, with ocular, bulbar, limb, and respiratory involvement varying among individuals. Initial symptoms often involve the extraocular muscles, leading to ptosis and diplopia in approximately 50% of cases at disease onset (Jaretzki et al., 2020). Some patients experience isolated ocular symptoms, a form known as ocular MG, while others progress to generalized MG, affecting additional muscle groups.

As the disease advances, bulbar muscle weakness can impair speech, chewing, and swallowing. Dysarthria and dysphagia increase the risk of aspiration, particularly in severe cases. Patients may struggle with clear enunciation, and speech often becomes slurred after prolonged conversation. Chewing fatigue, noticeable during meals, can impact nutritional intake and quality of life. Monitoring for aspiration pneumonia is essential (Sanders et al., 2016).

Limb and axial muscle weakness primarily affects proximal muscles, making tasks like climbing stairs, rising from a chair, or holding arms overhead challenging. Unlike primary myopathies, deep tendon reflexes remain intact, and sensory function is preserved, reinforcing the neuromuscular junction pathology. Symptoms often fluctuate throughout the day, with fatigue worsening in the evening or after repetitive activity.

Respiratory muscle involvement represents a severe manifestation, potentially leading to myasthenic crisis, a life-threatening condition requiring ventilatory support. Weakness of the diaphragm and intercostal muscles can cause dyspnea, particularly when lying flat or during exertion. Some patients report morning headaches due to nocturnal hypoventilation. Identifying early signs of respiratory compromise, such as reduced breath support for speech or paradoxical breathing patterns, is critical for timely intervention (Gilhus et al., 2019).

Neurological Examinations

A detailed neurological examination is essential for evaluating MG, as it reveals the distribution and fatigability of muscle weakness. Unlike myopathies or neurogenic disorders, MG presents with fluctuating weakness without sensory loss or reflex abnormalities. Assessing commonly affected muscles—extraocular, bulbar, and proximal limb muscles—helps establish clinical suspicion for further testing.

Ocular involvement is often the earliest sign, making eye movement assessments particularly informative. Patients may display unilateral or bilateral ptosis, worsening with sustained upward gaze. The Cogan’s lid twitch sign, a brief upward overshoot of the eyelid after a downward gaze, can indicate MG. Diplopia may emerge with prolonged lateral or vertical gaze, reflecting extraocular muscle weakness that fluctuates throughout the day. Unlike cranial nerve palsies, MG-related ophthalmoparesis lacks a fixed pattern, reinforcing the need for dynamic testing.

Bulbar muscle evaluation is crucial, as dysfunction in this region affects speech and swallowing. Counting aloud or reading continuously can reveal progressive dysarthria, with speech becoming increasingly nasal or slurred as fatigue sets in. Examination of palatal movement may show asymmetric elevation or reduced motion with repetitive phonation. Tongue weakness can manifest as impaired lateralization or atrophy in severe cases.

Limb and axial muscle testing focuses on detecting fatigability rather than isolated weakness. Standard strength assessments such as resisted shoulder abduction, hip flexion, and neck flexion are performed repeatedly to observe any decline over time. The “arm abduction test,” in which the patient holds their arms extended, can reveal progressive weakness characteristic of MG. The “chair rise test,” where the patient repeatedly stands from a seated position without using their arms, may highlight proximal muscle fatigability. Reflexes remain intact, and sensory deficits are absent, distinguishing MG from other neuromuscular conditions.

Laboratory Antibody Testing

Serological testing confirms MG by detecting autoantibodies targeting the neuromuscular junction. These antibodies help differentiate MG subtypes, which can influence treatment decisions. While most patients have detectable autoantibodies, some remain seronegative, requiring further diagnostic evaluation.

Acetylcholine Receptor

Acetylcholine receptor (AChR) antibodies are present in approximately 85% of generalized MG cases and 50% of ocular MG cases (Lindstrom et al., 2018). These antibodies disrupt neuromuscular transmission through complement activation, receptor internalization, and direct functional blockade. Testing is performed using radioimmunoassay or enzyme-linked immunosorbent assay (ELISA), with high specificity for MG. Low titers may occasionally be found in other autoimmune conditions, necessitating clinical correlation. The presence of AChR antibodies is associated with thymoma in some cases, warranting further imaging studies.

Muscle-Specific Kinase

Muscle-specific kinase (MuSK) antibodies are detected in 5-10% of MG cases, particularly in those seronegative for AChR antibodies (Hoch et al., 2020). Unlike AChR-associated MG, MuSK-positive MG predominantly affects bulbar, facial, and respiratory muscles, often leading to severe presentations. These antibodies impair neuromuscular transmission by disrupting agrin-mediated clustering of AChRs. Standard assays include radioimmunoprecipitation and cell-based assays, with the latter offering higher sensitivity. MuSK-positive MG responds poorly to acetylcholinesterase inhibitors but may improve with corticosteroids, plasma exchange, or rituximab.

Additional Biomarkers

In seronegative cases, testing for low-density lipoprotein receptor-related protein 4 (LRP4) antibodies may be considered. LRP4 antibodies are found in a subset of MG patients, particularly those with milder disease (Zhang et al., 2021). These antibodies impair AChR clustering at the neuromuscular junction. Striational antibodies, such as anti-titin and anti-ryanodine receptor antibodies, are often present in MG patients with thymoma and may indicate paraneoplastic disease.

Electrophysiological Evaluations

Electrophysiological testing provides objective evidence of neuromuscular transmission defects. Two primary techniques—repetitive nerve stimulation (RNS) and single-fiber electromyography (SFEMG)—assess synaptic transmission by evaluating muscle responses to nerve impulses.

RNS involves delivering electrical impulses to a motor nerve while recording muscle response. In MG, a decremental response occurs, with the compound muscle action potential (CMAP) amplitude declining by more than 10% after repeated stimulation at low frequencies. Sensitivity improves when testing proximal muscles, though patient discomfort and technical challenges may limit feasibility.

SFEMG offers greater sensitivity by detecting abnormal neuromuscular jitter, a measure of variability in muscle fiber response time. Increased jitter and impulse blocking indicate impaired neuromuscular transmission. SFEMG is particularly useful in seronegative MG, where definitive diagnostic markers may be lacking. While highly sensitive, SFEMG is less specific, as increased jitter can also be seen in other neuromuscular conditions.

Imaging Based Assessments

Imaging studies help identify associated abnormalities, particularly thymic pathology. Given the strong correlation between MG and thymic disorders, imaging is routinely performed to detect thymoma or thymic hyperplasia.

Computed tomography (CT) of the chest with contrast is the preferred initial imaging modality, offering detailed visualization of the anterior mediastinum. Thymomas, present in approximately 10-15% of MG patients (Marx et al., 2021), often appear as well-defined, lobulated masses. Magnetic resonance imaging (MRI) provides superior soft tissue contrast and is useful for further characterization of thymic lesions.

Positron emission tomography (PET) scans are not routinely used but may help distinguish between benign and malignant thymic lesions. If a thymoma is detected, surgical resection is typically recommended, as thymectomy has been shown to improve clinical outcomes in certain MG subtypes.

Pharmacological Testing

Pharmacological testing assesses neuromuscular transmission in suspected MG cases. The edrophonium test involves administering a short-acting acetylcholinesterase inhibitor to evaluate transient improvement in muscle strength. While effective for ocular MG, the test has fallen out of favor due to potential adverse effects.

Pyridostigmine, a longer-acting acetylcholinesterase inhibitor, is often used in a therapeutic trial to assess symptom responsiveness. A positive response, manifesting as reduced fatigue and improved muscle endurance, supports the diagnosis. However, a lack of response may indicate MuSK-positive MG, which tends to be less responsive to acetylcholinesterase inhibitors.