How should I evaluate and diagnose myasthenia gravis?

Evaluation and Diagnosis of Myasthenia Gravis

Begin with bedside ice pack testing and anti-acetylcholine receptor (AChR) antibody testing as your first-line diagnostic approach, followed by single-fiber EMG if antibodies are negative, as recommended by the American Academy of Neurology. 1

Clinical Examination: Key Features to Identify

Ocular Signs (Most Common Presentation)

• Fatigable ptosis that worsens with sustained upward gaze and improves after rest or ice application 2, 1
• Asymmetric diplopia from extraocular muscle weakness that fluctuates throughout the day 2
• Pupils must be normal—any pupillary abnormality immediately excludes myasthenia gravis and suggests third nerve palsy or other etiologies 2, 3

Bulbar Manifestations (High-Risk Features)

• Dysphagia is particularly concerning as it precedes myasthenic crisis in >50% of cases and requires urgent evaluation 3
• Dysarthria that worsens with prolonged speech 2
• Facial muscle weakness and hoarseness 2, 3

Limb and Respiratory Involvement

• Proximal > distal muscle weakness, with difficulty climbing stairs 2, 1
• Shortness of breath with light activity mandates immediate respiratory assessment with negative inspiratory force (NIF) and vital capacity (VC) 1
• Inability to count to 15 on a single breath signals imminent respiratory failure 3

Bedside Diagnostic Tests (Perform Immediately)

Ice Pack Test (Highly Specific)

• For ptosis: Apply ice pack over closed eyes for 2 minutes 3
• For strabismus/ophthalmoplegia: Apply for 5 minutes 3
• Positive test: ≥2 mm improvement in ptosis OR ≥50% reduction in ocular deviation 3
• This test has high specificity for myasthenia gravis and should be performed while awaiting serologic confirmation 1, 3

Rest Test

• Have patient close eyes for several minutes—improvement in ptosis or diplopia supports the diagnosis, though less standardized than ice pack test 3

Serologic Testing Algorithm

First-Line Antibody Testing

• Anti-AChR antibodies are present in 80-85% of generalized myasthenia gravis but only 40-50% of purely ocular cases 1, 3
• Anti-striated muscle antibodies should be included to identify patients at higher risk for thymoma 3

Second-Line Antibody Testing (If AChR Negative)

• Anti-MuSK antibodies—approximately one-third of seronegative patients will be MuSK-positive 1, 4
• Anti-LRP4 antibodies may be considered in seronegative cases 1, 4
• About 10% of patients remain seronegative for all known antibodies 4

Electrodiagnostic Studies

When to Order

• Perform when antibodies are negative despite strong clinical suspicion 1
• Single-fiber EMG (SFEMG) is the gold standard with >90% sensitivity for ocular myasthenia 1, 3
• A negative SFEMG is atypical and should prompt reconsideration of the differential diagnosis 3

Additional Electrodiagnostic Testing

• Repetitive nerve stimulation to multiple nerves before and after exercise helps identify neuromuscular junction disorders 5
• Nerve conduction studies and needle EMG exclude peripheral neuropathy and detect concurrent myositis 3

Pharmacologic Testing (Optional)

Edrophonium (Tensilon) Test

• Sensitivity of 86% for ocular myasthenia gravis 3
• Must have atropine 0.4-0.5 mg IV immediately available to treat muscarinic side effects (bradycardia, bronchospasm, excessive salivation) 3, 6
• Adults: Inject 0.2 mL (2 mg) IV over 15-30 seconds; if no reaction after 45 seconds, inject remaining 0.8 mL (8 mg) 6
• Children ≤75 lbs: 0.1 mL (1 mg) initial dose, titrate up to 0.5 mL (5 mg) 6

Empiric Pyridostigmine Trial

• Start at 30 mg orally three times daily 1, 3
• Important caveat: ~50% of ocular myasthenia patients show minimal response to pyridostigmine alone, so lack of response does not exclude the diagnosis 3

Comprehensive Workup for Confirmed Cases

Respiratory Assessment (Critical)

• Pulmonary function testing with NIF and vital capacity in all patients with generalized symptoms 1, 3
• Diminished cough strength and ineffective secretion clearance are indications for ICU admission 3

Cardiac Evaluation

• Troponin T, ECG, and echocardiogram to rule out myocarditis, especially if respiratory insufficiency or elevated CK is present 1, 3

Myositis Screening

• Creatine kinase (CK), aldolase, ESR, and CRP to evaluate for concurrent myositis 7, 1, 3

Neuroimaging

• Brain and/or spine MRI based on clinical symptoms to exclude CNS lesions mimicking myasthenia gravis 3
• Chest CT to evaluate for thymoma (present in 10-20% of AChR-positive patients) 4

Critical Medication Review

Immediately discontinue medications that worsen myasthenia gravis: 1, 3

• β-blockers
• IV magnesium
• Fluoroquinolones
• Aminoglycosides
• Macrolide antibiotics

Key Differential Diagnoses to Exclude

Third Nerve Palsy

• Distinguished by pupillary involvement (myasthenia spares pupils) 2, 3
• Requires immediate neuroimaging for aneurysm or ischemia 3

Thyroid Eye Disease

• Presents with proptosis, eyelid retraction, and mechanical restriction on forced duction testing 3
• Orbital imaging shows tendon-sparing muscle enlargement 3

Lambert-Eaton Syndrome

• Distinguished by autonomic symptoms and improvement with repeated muscle use (opposite of myasthenia) 8

Botulism

• Symmetric cranial nerve palsies with gastrointestinal symptoms 3

Common Pitfalls to Avoid

• Do not rely solely on antibody testing—50% of ocular myasthenia cases are seronegative for AChR antibodies 3
• Do not dismiss the diagnosis if pyridostigmine fails—50% of ocular cases show minimal response 3
• Do not delay respiratory assessment—dysphagia and bulbar weakness precede crisis in >50% of cases 3
• Always check pupils—pupillary abnormalities exclude myasthenia gravis 2, 3

Prognosis and Monitoring

• 50-80% of patients with isolated ocular symptoms progress to generalized myasthenia within 2 years 1, 3
• Regular pulmonary function monitoring is essential in all generalized cases 1
• Median duration of mechanical ventilation in myasthenic crisis is 12-14 days 3

Urgent Neurology Consultation

Obtain urgent neurology consultation for: 1

• All confirmed cases of myasthenia gravis
• Any patient with respiratory symptoms or dysphagia
• Suspected myasthenic crisis (severe weakness, respiratory distress)