How do I confirm a diagnosis of myasthenia gravis?

How to Confirm Myasthenia Gravis

Begin with serologic testing for anti-acetylcholine receptor (AChR) antibodies, which confirms the diagnosis in approximately 80% of generalized MG cases, followed by electrodiagnostic studies and bedside clinical tests when antibodies are negative or when ocular symptoms predominate. 1, 2

Initial Serologic Testing Algorithm

Step 1: Anti-AChR Antibodies

• Order anti-AChR antibodies as the first-line test, which are present in 80-85% of generalized MG but only 50% of purely ocular MG. 1, 2
• Include anti-striated muscle antibodies in the initial panel, as these help identify patients at higher risk for thymoma. 3, 1

Step 2: If AChR Antibodies Are Negative

• Immediately reflex to anti-muscle-specific kinase (MuSK) antibodies, as approximately one-third of seronegative patients will be MuSK-positive. 1, 2
• Consider anti-lipoprotein receptor-related protein 4 (LRP4) antibodies, which are found in 2-50% of double-seronegative cases. 1, 4

Electrodiagnostic Confirmation

Single-Fiber Electromyography (SFEMG)

• SFEMG is the gold standard with >90% sensitivity for ocular MG and should be performed when serologic tests are negative or when diagnostic certainty is needed. 1, 5, 2
• A negative SFEMG result is atypical and warrants careful reconsideration of the differential diagnosis. 1

Repetitive Nerve Stimulation (RNS)

• RNS is less sensitive (positive in only one-third of ocular cases) but more widely available than SFEMG. 5, 2
• Include nerve conduction studies and needle EMG to exclude peripheral neuropathy and evaluate for concurrent myositis. 3, 1

Bedside Clinical Tests

Ice Pack Test (Highly Specific)

• Apply an ice pack over closed eyelids for 2 minutes for ptosis or 5 minutes for strabismus/ophthalmoplegia. 1, 5, 2
• Measure baseline ptosis using marginal reflex distance (MRD) and quantify ocular misalignment in prism diopters before ice application. 1
• A positive test shows improvement of ptosis by ≥2 mm or reduction in ocular deviation by ≥50% (or ≥10 prism diopters when baseline exceeds 20 PD). 1
• This test is highly specific because cooling slows acetylcholine breakdown, allowing limited acetylcholine to remain longer in the synaptic cleft. 1

Edrophonium (Tensilon) Test

• Administer 0.2 mL (2 mg) IV initially; if no reaction after 45 seconds, inject remaining 0.8 mL (8 mg). 6
• Sensitivity is 95% for generalized MG and 86% for ocular MG. 5, 2
• Must have atropine 0.4-0.5 mg IV immediately available to treat muscarinic side effects (excessive tearing, salivation, bradycardia, bronchospasm). 3, 6
• This test requires experienced practitioners in a monitored setting due to potential adverse effects. 5, 6

Essential Supplementary Workup

Respiratory Assessment

• Measure pulmonary function with negative inspiratory force (NIF) and vital capacity (VC) to assess respiratory muscle involvement, as dysphagia and bulbar weakness precede myasthenic crisis in >50% of cases. 3, 1, 2
• Test the patient's ability to count to 15 on a single breath—inability indicates imminent respiratory insufficiency. 1

Cardiac Evaluation

• Check troponin T, perform ECG, and consider transthoracic echocardiogram if respiratory insufficiency or elevated CPK is present to rule out concomitant myocarditis. 3, 1, 2

Screening for Myositis

• Measure creatine phosphokinase (CPK), aldolase, ESR, and CRP to evaluate for possible concurrent myositis. 3, 1, 2

Imaging Studies

• Obtain CT chest with contrast after diagnosis confirmation to evaluate for thymoma, which occurs in 10-20% of AChR-positive patients. 5, 2
• Consider MRI of brain and/or spine based on symptoms to exclude CNS lesions that could mimic MG. 3, 1

Critical Diagnostic Pitfalls to Avoid

Pupillary Examination

• Pupils are characteristically NOT affected in MG—this is a key distinguishing feature from third nerve palsy. 1
• If pupils are abnormal, immediately prioritize evaluation for third nerve palsy, Horner syndrome, or other neurologic causes over MG. 1

Medication Review

• Immediately identify and discontinue medications that worsen MG: β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics. 3, 1, 2

Seronegative Cases

• Approximately 10-15% of MG patients remain seronegative for all known antibodies despite having true MG. 7, 8, 9
• In these cases, diagnosis relies heavily on clinical presentation, positive ice pack test, and abnormal SFEMG findings. 1, 2

Prognostic Considerations

• 50-80% of patients presenting with isolated ocular symptoms will progress to generalized MG within a few years, most commonly within the first two years. 1, 5, 2
• This high progression rate mandates comprehensive workup even when symptoms appear limited to ocular muscles. 1