Treatment of Grade 3-4 Myasthenia Gravis
For Grade 3-4 myasthenia gravis, you must permanently discontinue any immune checkpoint inhibitors, admit the patient to an ICU-capable unit, and immediately initiate IVIG at 2 g/kg total dose over 5 days (0.4 g/kg/day × 5 days) or plasmapheresis for 5 days, while continuing corticosteroids concurrently. 1
Immediate Management Algorithm
Critical First Steps
- Permanently discontinue immune checkpoint inhibitors if the myasthenia is immune-related adverse event (irAE)-associated 1
- Admit to hospital with ICU-level monitoring capability given the high risk of respiratory compromise 1, 2
- Obtain urgent neurology consultation 1
Acute Immunotherapy (Choose One)
- IVIG: 2 g/kg total dose administered as 0.4 g/kg/day for 5 consecutive days 1, 2, 3
- Plasmapheresis: 20-25 mL/kg for 5 sessions 1, 4
Both IVIG and plasmapheresis have comparable efficacy for Grade 3-4 disease 1. IVIG is specifically preferred when plasmapheresis is contraindicated or not feasible, including patients with hypotension, autonomic instability, sepsis, advanced age (>65 years), or pregnancy 2, 5. Sequential therapy (plasmapheresis followed by IVIG) provides no additional benefit and should be avoided 2.
Concurrent Corticosteroid Therapy
- Continue or initiate corticosteroids (methylprednisolone 2-4 mg/kg/day or prednisone 1-1.5 mg/kg/day) during IVIG or plasmapheresis 1, 2
- Taper gradually based on symptom improvement 1
Symptomatic Management
- Continue pyridostigmine if the patient can take oral medications, though it may be withheld if intubation is required 2
- Standard dosing: 30 mg orally three times daily, titrating to maximum 120 mg four times daily 1, 2
Essential Monitoring Requirements
Respiratory Surveillance
- Perform frequent pulmonary function assessments with negative inspiratory force and vital capacity monitoring 1, 2, 3
- This is critical given the potential for rapid progression to respiratory failure requiring mechanical ventilation 1
Neurologic Assessment
Cardiac Monitoring
- Check troponin T and perform ECG with transthoracic echocardiogram if there is respiratory insufficiency or elevated CPK, as concomitant myocarditis can occur 1
Diagnostic Workup (If Not Already Completed)
- Acetylcholine receptor (AChR) and antistriated muscle antibodies; if AChR negative, test for muscle-specific kinase (MuSK) and lipoprotein-related protein 4 (LRP4) antibodies 1, 6
- Creatine phosphokinase (CPK), aldolase, ESR, and CRP to evaluate for concurrent myositis 1
- Electrodiagnostic studies including repetitive nerve stimulation and/or single-fiber EMG 1, 6
- MRI of brain and/or spine if symptoms suggest CNS involvement 1
Critical Medications to Avoid
Strictly avoid medications that worsen neuromuscular transmission, as they can precipitate myasthenic crisis 1, 2, 3:
- β-blockers 1, 2
- Intravenous magnesium 1, 2
- Fluoroquinolone antibiotics 1, 2
- Aminoglycoside antibiotics 1, 2
- Macrolide antibiotics 1, 2
- Metoclopramide 2
Important Clinical Considerations
IVIG Is NOT for Chronic Maintenance
IVIG should not be used for chronic maintenance therapy in myasthenia gravis 2, 3. It is reserved exclusively for acute exacerbations (Grade 3-4) or myasthenic crisis 2, 3. The American Academy of Neurology explicitly recommends against chronic IVIG use, with strong evidence supporting this restriction 2, 3.
Prognosis and Follow-up
- Grade 3-4 myasthenia represents severe generalized weakness with limitation of self-care, dysphagia, or facial weakness 6
- Immune checkpoint inhibitor-associated myasthenia may be monophasic, potentially not requiring additional corticosteroid-sparing agents long-term 1
- Regular neurology follow-up is essential to adjust immunosuppression and monitor for disease progression 2
Common Pitfall
The most critical error is delaying IVIG/plasmapheresis while attempting to optimize pyridostigmine and corticosteroids alone in Grade 3-4 disease. Grade 3-4 myasthenia requires immediate acute immunotherapy given the risk of rapid progression to respiratory failure 1, 2, 3.