In a patient with myasthenia gravis who remains weak despite maximal pyridostigmine dosing, what are the recommended next symptomatic and immunosuppressive treatment options?

Management of Myasthenia Gravis Not Responding to Pyridostigmine

For patients with myasthenia gravis who remain symptomatic despite maximal pyridostigmine dosing (120 mg four times daily), initiate corticosteroids immediately with prednisone 1–1.5 mg/kg orally daily, and if symptoms are severe (Grade 3–4) with dysphagia, facial weakness, or respiratory involvement, admit for ICU-level monitoring and administer IVIG 2 g/kg IV over 5 days or plasmapheresis. 1

Severity-Based Treatment Algorithm

Grade 2 Disease (Mild Generalized Weakness)

• Add corticosteroids directly if pyridostigmine at maximum dose (120 mg four times daily) provides insufficient symptom control 1
• Start prednisone 1–1.5 mg/kg orally daily and taper gradually based on symptom improvement 1
• Continue pyridostigmine at current dose while initiating corticosteroids 1
• Obtain neurology consultation to guide immunosuppressive therapy 1

Grade 3–4 Disease (Severe Weakness or Crisis)

Immediate Actions:

• Admit to hospital with ICU-level monitoring capability for any patient with limiting self-care activities, dysphagia, facial weakness, respiratory muscle weakness, or rapidly progressive symptoms 1
• Obtain urgent neurology consultation 1
• Initiate IVIG 2 g/kg IV over 5 days (0.4 g/kg/day) OR plasmapheresis for 5 days 1
• Continue or initiate high-dose corticosteroids (methylprednisolone 1–2 mg/kg IV daily) 1
• Perform frequent pulmonary function assessment with negative inspiratory force and vital capacity monitoring 1
• Conduct daily neurologic review 1

Critical Respiratory Assessment

Recognize impending crisis early:

• Dysphagia is present in >50% of patients preceding myasthenic crisis and serves as a key warning sign for respiratory failure 2
• Inability to count to 15 on a single breath indicates imminent respiratory insufficiency requiring urgent evaluation 2
• Diminished cough strength and ineffective secretion clearance mandate ICU admission due to aspiration risk 2
• Median duration of mechanical ventilation in myasthenic crisis is 12–14 days, with 22% requiring ventilation within the first week 2

Medication Safety

Immediately discontinue or avoid these medications that worsen myasthenia:

• β-blockers 1
• Intravenous magnesium 1
• Fluoroquinolone antibiotics 1
• Aminoglycoside antibiotics 1
• Macrolide antibiotics 1

Choice Between IVIG and Plasmapheresis

Both are equally effective for acute exacerbations:

• IVIG is preferred in pregnant women and when plasmapheresis access is limited 3
• Plasmapheresis may be more cost-effective in resource-limited settings but requires specialized equipment and trained personnel 3
• Sequential therapy (plasmapheresis followed by IVIG) is no more effective than either alone and should be avoided 3

Long-Term Immunosuppression Considerations

After acute stabilization with IVIG/plasmapheresis and corticosteroids:

• Most patients eventually require long-term immunosuppressive therapy beyond pyridostigmine and corticosteroids 4
• Azathioprine is commonly used as a corticosteroid-sparing agent for moderate to severe disease 2
• IVIG should NOT be used for chronic maintenance therapy in myasthenia gravis 3
• Immune checkpoint inhibitor-associated myasthenia may be monophasic and not require additional corticosteroid-sparing agents 1

Common Pitfalls to Avoid

Pyridostigmine limitations:

• Approximately 50% of patients with ocular myasthenia show minimal response to pyridostigmine alone, which does not exclude the diagnosis 2
• Pyridostigmine provides only partial benefit in most patients and should not delay initiation of immunosuppressive therapy in Grade 2 or higher disease 4
• Do not continue escalating pyridostigmine beyond 120 mg four times daily; instead, add corticosteroids 1

Diagnostic workup before escalation:

• Confirm diagnosis with anti-AChR antibodies, anti-striated muscle antibodies 2
• If AChR-negative, test for anti-MuSK and anti-LRP4 antibodies 3, 2
• Perform electrodiagnostic studies including repetitive nerve stimulation and single-fiber EMG 1, 2
• Check cardiac troponin and ECG if respiratory insufficiency or elevated CPK to rule out concurrent myocarditis 1

Monitoring During Treatment Escalation

• Pulmonary function testing with negative inspiratory force and vital capacity, especially with any respiratory symptoms 3, 2
• Daily neurologic examination in hospitalized patients 1
• Gradual corticosteroid taper based on symptom improvement, not fixed schedule 1
• Pyridostigmine can be weaned as corticosteroids take effect 1