What is the management of myasthenia gravis?

Myasthenia Gravis: Clinical Overview and Management

Definition and Pathophysiology

Myasthenia gravis is an autoimmune neuromuscular disorder caused by antibodies targeting the postsynaptic neuromuscular junction, most commonly against acetylcholine receptors (AChR), resulting in fatigable muscle weakness. 1

• Antibodies may target AChR (most common), muscle-specific kinase (MuSK), or lipoprotein-related protein 4 (LRP4) 2, 3
• The autoimmune attack destroys elements of the postsynaptic membrane, decreasing nerve-impulse transmission and causing progressive muscle weakness with activity 4, 1

Clinical Presentation

Cardinal Features

• Fatigable or fluctuating muscle weakness, typically more proximal than distal 5
• Weakness worsens with repetitive activity and improves with rest 1
• Pupils are characteristically spared - this is a critical distinguishing feature from third nerve palsy or other causes of ophthalmoplegia 5

Specific Symptom Patterns

• Ocular involvement (50% present with ocular symptoms): ptosis, diplopia, extraocular movement abnormalities 5, 6
• Bulbar symptoms: dysphagia, dysarthria, facial muscle weakness, drooling, hoarseness 2, 5
• Generalized weakness: difficulty climbing stairs, proximal limb weakness 5
• Respiratory muscle involvement: shortness of breath, respiratory insufficiency in severe cases 2

Critical Warning Sign

• 50-80% of patients with initial ocular symptoms may progress to generalized myasthenia within a few years 5

Diagnostic Workup

Serological Testing

• First-line: AChR antibodies and antistriated muscle antibodies 2, 3
• If AChR negative: Test for MuSK and LRP4 antibodies 2, 3
• Approximately 30-50% of patients with thymomas have myasthenia gravis 5

Electrodiagnostic Studies

• Single-fiber EMG is the gold standard with >90% sensitivity in ocular myasthenia 7
• Repetitive nerve stimulation testing (positive in only one-third of ocular myasthenia cases) 7
• Neuromuscular junction testing with repetitive stimulation and/or jitter studies 2

Bedside Testing

• Ice pack test: Apply ice pack over closed eyes for 2 minutes - highly specific for ocular myasthenia gravis 5

Additional Workup

• Pulmonary function testing with negative inspiratory force and vital capacity 2, 3
• Creatine phosphokinase (CPK), aldolase, ESR, CRP to evaluate for concurrent myositis 2
• If respiratory insufficiency or elevated CPK/troponin: ECG and echocardiogram to rule out myocarditis 2
• MRI of brain/spine if symptoms suggest CNS involvement 2
• Neurology consultation is mandatory 2

Management Algorithm

Grade 2 (Mild to Moderate Symptoms)

Symptoms interfering with activities of daily living, ocular symptoms only, or mild generalized weakness (MGFA class 1-2):

First-Line: Pyridostigmine

• Start pyridostigmine 30 mg orally three times daily 2, 3
• Gradually titrate to maximum 120 mg orally four times daily based on symptoms and tolerance 2, 3
• This is FDA-approved for myasthenia gravis treatment 8
• Approximately 50% of patients with ocular myasthenia show minimal response to pyridostigmine alone 5, 7

Second-Line: Add Corticosteroids

• If pyridostigmine provides insufficient control, initiate prednisone 1-1.5 mg/kg orally daily 2, 3
• 66-85% of patients respond to corticosteroids 5, 7
• Taper gradually based on symptom improvement 2, 3
• May hold immune checkpoint inhibitors (if applicable) and resume only if symptoms resolve 2

Grade 3-4 (Severe/Crisis)

Limiting self-care, weakness limiting walking, ANY dysphagia, facial weakness, respiratory muscle weakness, rapidly progressive symptoms, or myasthenic crisis (MGFA class 3-4):

Immediate Actions

• Permanently discontinue immune checkpoint inhibitors (if applicable) 2
• Admit to hospital with ICU-level monitoring capability 2, 3
• Mandatory neurology consultation 2

Acute Treatment

• Continue corticosteroids AND initiate IVIG 2 g/kg IV over 5 days (0.4 g/kg/day × 5 days) OR plasmapheresis for 5 days 2, 3
• Continue pyridostigmine during acute treatment 3

Monitoring Requirements

• Frequent pulmonary function assessment with negative inspiratory force and vital capacity 2, 3
• Daily neurologic evaluations 2, 3
• Monitor for autonomic dysfunction 2
• Cardiac monitoring if myocarditis suspected 2

Long-Term Immunosuppression

• Azathioprine is effective for long-term steroid-sparing therapy 5, 7, 9
• Other options include cyclosporine, mycophenolate mofetil, methotrexate, tacrolimus 9, 10
• Rituximab reserved for refractory disease 9, 6, 10
• Efgartigimod alfa-fcab recently approved for AChR-positive patients 7

Thymectomy

• Clear evidence supports thymectomy in AChR-positive generalized MG up to age 65 years 6
• Consider evaluation for thymectomy in appropriate patients 5

Critical Medications to AVOID

These medications can precipitate myasthenic crisis and must be strictly avoided: 2, 3

• β-blockers 2, 3
• Intravenous magnesium 2, 3
• Fluoroquinolone antibiotics 2, 3
• Aminoglycoside antibiotics 2, 3
• Macrolide antibiotics 2, 3
• Barbiturate-containing medications (e.g., butalbital) 3

Important Clinical Pitfalls

Cholinergic Crisis vs. Myasthenic Crisis

• Both present with severe muscle weakness, making differentiation extremely difficult 8
• Cholinergic crisis results from pyridostigmine overdosage and requires immediate withdrawal of all anticholinesterase drugs 8
• Myasthenic crisis requires MORE intensive anticholinesterase therapy 8
• Edrophonium chloride testing may be needed for differentiation 8
• Atropine is used for cholinergic crisis but can mask signs of overdosage 8

Preoperative Considerations

• Any patient with suspected myasthenia requiring surgery MUST have serum AChR antibody levels measured preoperatively to avoid respiratory failure during anesthesia 5
• Exercise extreme caution with anesthetic agents in patients with respiratory muscle weakness 7

IVIG Misuse

• IVIG should NOT be used for chronic maintenance therapy in myasthenia gravis 3
• IVIG is reserved for acute exacerbations (Grade 3-4) requiring hospitalization 3
• The correct dose is 2 g/kg total over 5 days, NOT ongoing maintenance dosing 3

Patient Education Priorities

• Take pyridostigmine exactly as prescribed for optimal symptom control 3
• Plan activities around medication timing when strength is optimal 3
• Seek immediate medical attention for worsening weakness, speech/swallowing changes, or respiratory difficulties 3
• Understand that crises may require ICU admission with IVIG or plasmapheresis 3
• Regular neurological follow-up is mandatory to adjust treatment 3

Special Populations

Pregnancy

• Pregnancy carries 40% risk of MG exacerbation during pregnancy and additional 30% risk postpartum 4
• Maternal mortality risk approximately 40 per 1,000 live births 4
• Perinatal mortality approximately 68 per 1,000 births 4
• Pyridostigmine safety in pregnancy not established - weigh benefits against risks 8
• Anticholinesterase medications and corticosteroids remain mainstays of therapy 4
• Meticulous prenatal surveillance and early detection of exacerbations are critical 4

Elderly Patients

• Comorbidity is frequent, particularly in elderly patients 1
• Treatment decisions must account for specific comorbidities 6

Prognosis and Goals

• Treatment should aim for clinical remission or minimal manifestations with near-normal function and quality of life 6, 1
• Active physical training should be encouraged 1
• Fatigue is common and should be distinguished from fatigable weakness; manage with physical therapy with or without psychological support 6
• Address dysfunctional breathing with respiratory physiotherapy techniques 6