Myasthenia Gravis Workup and Management
Initial Diagnostic Approach
Begin with bedside clinical testing—specifically the ice pack test—which is highly specific for myasthenia gravis and can be performed immediately in any clinical setting. 1, 2
Key Clinical Features to Identify
- Fluctuating, fatigable weakness that worsens with activity and improves with rest, particularly affecting ocular, bulbar, and proximal limb muscles 2, 3
- Ptosis that worsens with sustained upgaze (>60 seconds) and may demonstrate Cogan lid-twitch sign 1, 3
- Variable diplopia and strabismus that changes pattern during examination or with fatigue 1, 3
- Pupils are characteristically spared—any pupillary abnormality should immediately redirect you toward third nerve palsy or other diagnoses 2, 3
- Slow ocular saccades on examination 1
- Dysphagia, dysarthria, or facial weakness indicating bulbar involvement 2, 3
- Proximal > distal limb weakness, particularly difficulty climbing stairs or holding up the head 2, 3
Critical Red Flags Requiring Urgent Evaluation
- Dysphagia with aspiration risk—present in >50% of cases preceding myasthenic crisis 2
- Respiratory symptoms including shortness of breath with light activity, as respiratory failure is life-threatening 2, 3
- Neck or respiratory muscle weakness 3
Diagnostic Testing Algorithm
Step 1: Bedside Clinical Tests (Perform Immediately)
- Ice pack test: Apply ice over closed eyes for 2 minutes (ptosis) or 5 minutes (strabismus); improvement of ≥2 mm ptosis or reduced misalignment is highly specific 1, 2
- Rest test (without ice) can also provide supportive diagnostic information 1, 2
- Edrophonium (Tensilon) test (86% sensitivity for ocular MG): Must be performed in monitored setting with atropine 0.4-0.5 mg IV immediately available for muscarinic side effects (bradycardia, bronchospasm, hypotension) 2
Step 2: Serologic Testing (Order Stat)
- Anti-acetylcholine receptor (AChR) antibodies: Present in 80-85% of generalized MG but only 40-77% of ocular MG 2, 4, 5
- If AChR-negative, order anti-MuSK antibodies: Positive in approximately one-third of seronegative cases 2, 4
- Anti-LRP4 antibodies: Consider in double-seronegative patients 2, 4
- Anti-striated muscle antibodies: Associated with thymoma risk 2
Critical pitfall: A negative AChR antibody does NOT exclude myasthenia gravis, especially in ocular disease where 50% are seronegative 2
Step 3: Electrodiagnostic Studies
- Single-fiber EMG: Gold standard with >90% sensitivity for ocular MG; a negative result is atypical and warrants reconsideration of diagnosis 2
- Repetitive nerve stimulation: Shows decremental response in MG 2, 5
Step 4: Imaging and Additional Workup
- Chest CT: Screen for thymoma (present in 10-20% of AChR-positive patients); thymectomy is indicated if thymoma present 2, 4, 5
- Pulmonary function tests (NIF and vital capacity): Essential in all generalized MG to monitor respiratory status 2
- Cardiac evaluation (troponin, ECG, echocardiography): If respiratory insufficiency, elevated CPK, or concern for myocarditis/myositis 2, 4
Management Algorithm
Classification by MGFA Severity
Use MGFA classification to guide treatment intensity: 2
- Class I: Ocular symptoms only
- Class II: Mild generalized weakness
- Class III: Moderate generalized weakness
- Class IV: Severe generalized weakness
- Class V: Myasthenic crisis requiring intubation
Treatment for MGFA Class I (Ocular Only)
Start pyridostigmine 30 mg orally three times daily, gradually increasing to maximum 120 mg four times daily as tolerated. 2, 4
- Critical limitation: Only ~50% of ocular MG patients respond adequately to pyridostigmine alone 2
- If inadequate response after trial: Escalate to prednisone 1-1.5 mg/kg daily 2
- Monitor closely: 50-80% progress to generalized MG within 2 years, most commonly within first 2 years 1, 2
Treatment for MGFA Class II-III (Mild to Moderate Generalized)
Initiate combination therapy with pyridostigmine PLUS prednisone 1-1.5 mg/kg orally daily. 2
- Corticosteroids produce favorable response in 66-85% of patients 4
- Taper prednisone gradually based on symptom improvement 2
- Add azathioprine as steroid-sparing agent if inadequate response or to reduce chronic steroid dependence 2, 4
Treatment for MGFA Class IV-V (Severe/Crisis)
Admit to ICU-level monitoring immediately and obtain urgent neurology consultation. 2
- Acute immunotherapy: IVIG 2 g/kg over 5 days OR plasmapheresis 2
- High-dose corticosteroids 2
- Permanently discontinue any immune checkpoint inhibitors if present 2
- Intubation and mechanical ventilation for Class V 2
Thymectomy Considerations
Thymectomy is indicated when thymoma is identified on chest CT and can substantially reduce MG symptoms even without thymoma in specific age-based and immune-based characteristics. 1, 4
Critical Medications to AVOID
The following drugs can precipitate or worsen myasthenic crisis and must be avoided: 2
- β-blockers
- IV magnesium
- Fluoroquinolones
- Aminoglycosides
- Macrolide antibiotics
Pyridostigmine Safety Considerations
Overdosage of pyridostigmine can cause cholinergic crisis—characterized by increasing muscle weakness leading to respiratory failure—which is difficult to distinguish from myasthenic crisis. 6
- Cholinergic crisis requires immediate withdrawal of all anticholinesterase drugs and atropine administration 6
- Myasthenic crisis requires more intensive anticholinesterase therapy—the treatments are opposite 6
- Differentiation may require edrophonium test and clinical judgment 6
- Atropine can mask signs of overdosage, leading to inadvertent cholinergic crisis 6
Monitoring and Follow-Up
- Regular pulmonary function testing (NIF, vital capacity) in all generalized MG 2
- Screen for concurrent autoimmune conditions (thyroid disease, SLE, rheumatoid arthritis) 2
- Monitor for myositis/myocarditis with CPK, aldolase, troponin if indicated 2, 4
- Assess for thymoma with chest CT at diagnosis 2, 4
Referral and Collaborative Care
All suspected myasthenia gravis requires urgent neurology referral—primary care should NOT initiate disease-specific therapy. 4