How should I diagnose myasthenia gravis in an adult or adolescent presenting with fluctuating ocular or generalized weakness such as ptosis, diplopia, or dysphagia?

Diagnosis of Myasthenia Gravis

Diagnose myasthenia gravis through a combination of clinical features (fluctuating, fatigable weakness with ocular or bulbar involvement), bedside testing (ice pack test), serologic antibody testing (AChR, MuSK, LRP4), and electrodiagnostic studies (single-fiber EMG), while immediately assessing for respiratory compromise in any patient with generalized symptoms. 1

Clinical Presentation: Key Features to Identify

Ocular Manifestations (Most Common Initial Presentation)

• Ptosis that worsens with prolonged upgaze or as the day progresses is often the first symptom, appearing unilateral or bilateral 1, 2
• Diplopia from extraocular muscle weakness that is highly variable in pattern and changes during examination 1
• Variable strabismus that shifts between examination positions—this "great masquerader" quality can mimic any pupil-sparing ocular motility disorder 1
• Slow saccades (rapid eye movements) are characteristic findings 1
• Pupils are NEVER affected—pupillary involvement immediately rules out myasthenia and suggests third nerve palsy or other neurologic causes 2

Bulbar and Generalized Symptoms

• Dysarthria (slurred speech) and dysphagia (difficulty swallowing) that worsen with prolonged talking or chewing 1
• Facial weakness with reduced facial expressions 1
• Proximal limb weakness affecting shoulders and hips more than distal muscles 1
• Neck weakness causing difficulty holding up the head 1
• Respiratory muscle weakness—the most life-threatening manifestation that can rapidly progress to respiratory failure 1

Hallmark Clinical Characteristics

• Fluctuating weakness that varies throughout the day and between examinations 1
• Fatigability with symptoms worsening with continued activity and improving with rest 1
• Diurnal variation with symptoms typically worse later in the day 3

Critical Red Flags Requiring Immediate Action

• Severe dysphagia with aspiration risk indicates impending myasthenic crisis 1
• Shortness of breath with light activity or inability to count to 15 on a single breath signals imminent respiratory insufficiency 2
• Diminished cough strength and ineffective secretion clearance warrant ICU admission 2
• Any patient with bulbar or respiratory symptoms requires urgent pulmonary function testing (negative inspiratory force, vital capacity) 4, 1

Bedside Diagnostic Tests

Ice Pack Test (Highly Specific)

• Apply ice pack over closed eyelids for 2 minutes when assessing ptosis 2
• Apply ice pack for 5 minutes when assessing strabismus or ophthalmoplegia 2
• Positive test: improvement of ptosis by ≥2 mm OR reduction in ocular deviation by ≥50% (or ≥10 prism diopters if baseline >20 PD) 2
• Mechanism: cooling slows acetylcholine breakdown, allowing limited acetylcholine to remain longer in the synaptic cleft 2
• This test is highly specific for myasthenia gravis 1, 2

Rest Test

• Have patient keep eyes closed for several minutes without ice—improvement in ptosis or strabismus supports diagnosis, though less standardized than ice pack test 2

Edrophonium (Tensilon) Test

• 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) 5
• Children ≤75 lbs: 0.1 mL (1 mg) initial dose, titrate up to 0.5 mL (5 mg) in 0.1 mL increments every 30-45 seconds 5
• Children >75 lbs: 0.2 mL (2 mg) initial dose, titrate up to 1 mL (10 mg) 5
• Sensitivity: 86% for ocular myasthenia 2
• Must have atropine 0.4-0.5 mg IV immediately available to treat muscarinic side effects (excessive tearing, salivation, bradycardia, bronchospasm, hypotension) 5
• Positive response: increased muscle strength, improved ptosis/diplopia 5

Serologic Testing (Order in All Suspected Cases)

First-Line Antibody Testing

• Acetylcholine receptor (AChR) antibodies: positive in 80-85% of generalized MG but only 40-77% of ocular MG 1, 6, 7
• Negative AChR does NOT exclude diagnosis—approximately 50% of purely ocular MG patients are seronegative 2, 6

Second-Line Antibody Testing (If AChR Negative)

• Muscle-specific kinase (MuSK) antibodies: positive in approximately one-third of seronegative patients 1, 2, 6
• Lipoprotein-related protein 4 (LRP4) antibodies: associated with both generalized and ocular MG 1, 2

Electrodiagnostic Studies

• Single-fiber EMG: sensitivity >90% for ocular myasthenia—the gold standard electrodiagnostic test 1, 2
• Repetitive nerve stimulation: positive in only one-third of ocular myasthenia cases, more useful in generalized MG 6, 7
• These studies are operator-dependent and require specialized equipment and expertise 2

Essential Imaging and Additional Work-Up

Chest Imaging (Mandatory)

• Chest CT to screen for thymoma—present in 10-20% of MG patients 1, 2, 7
• Thymoma requires different management and is a critical finding 1

Cardiac Evaluation (If Indicated)

• Check troponin, CPK, aldolase if respiratory insufficiency or elevated CPK present 1
• Obtain ECG and echocardiography to evaluate for concurrent myocarditis—particularly in immune checkpoint inhibitor-associated MG 1

Neuroimaging

• Brain MRI may help exclude brainstem strokes or other central lesions that mimic MG 2
• Consider if atypical features or concern for alternative diagnosis 4

Lumbar Puncture

• CSF is typically normal in MG—this distinguishes it from Guillain-Barré syndrome where CSF protein is elevated by week 2 2

Differential Diagnosis: Critical Distinctions

Third Nerve Palsy

• Pupillary involvement distinguishes this from MG (pupils spared in MG) 2
• Requires immediate neuroimaging and vascular work-up given aneurysm or ischemia risk 2

Thyroid Eye Disease

• Proptosis, eyelid retraction, mechanical restriction on forced duction testing 2
• Orbital imaging shows tendon-sparing muscle enlargement (versus normal imaging in MG) 2

Guillain-Barré Syndrome

• Ascending weakness, sensory involvement, absent/reduced reflexes 4
• Elevated CSF protein with normal WBC count 4
• Nerve conduction studies show acute polyneuropathy 4

Botulism

• Symmetric cranial nerve palsies, early gastrointestinal symptoms, descending paralysis 2
• Pupillary involvement (unlike MG) 1

Lambert-Eaton Syndrome

• Weakness improves with repeated muscle contraction (opposite of MG) 2
• Associated with small cell lung cancer 2

Diagnostic Algorithm

1. Establish clinical suspicion: fluctuating, fatigable weakness with ocular/bulbar involvement and normal pupils 1

2. Perform bedside testing: ice pack test (2-5 minutes) looking for ≥2 mm ptosis improvement or ≥50% reduction in strabismus 2

3. Order serologic testing: AChR antibodies first; if negative, add MuSK and LRP4 antibodies 1, 2

4. Obtain electrodiagnostic confirmation: single-fiber EMG (>90% sensitivity) or repetitive nerve stimulation 2

5. Screen for thymoma: chest CT in all patients 1, 2

6. Assess respiratory function: pulmonary function tests (NIF, vital capacity) if any generalized symptoms 4, 1

7. Consider edrophonium test: if diagnosis remains uncertain after above testing and expertise available 5

Common Pitfalls to Avoid

• Do not exclude MG based on negative AChR antibodies alone—50% of ocular MG is seronegative 2, 6
• Do not miss early respiratory involvement—failure to recognize this can be fatal; all grades warrant thorough respiratory evaluation 1
• Do not assume ocular symptoms will remain localized—50-80% progress to generalized MG within a few years, most within first 2 years 2
• Do not overlook medication history—beta-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolides can precipitate or worsen myasthenic weakness 4, 1, 2
• Do not forget to check for thymoma—present in 10-20% and requires surgical management 1, 7
• Do not perform edrophonium test without atropine immediately available—muscarinic side effects can be life-threatening 5

Prognosis and Natural History

• 50% of MG patients initially present with ocular symptoms only 1
• 50-80% of those with initial ocular symptoms develop generalized MG within a few years 1, 2
• Respiratory failure requiring ventilatory support can occur in severe cases (myasthenic crisis) 1
• Median duration of mechanical ventilation in myasthenic crisis is 12-14 days 2