What are the treatment options for Myasthenia Gravis (MG)?

Myasthenia Gravis: Comprehensive Treatment Approach

Diagnostic Confirmation

Before initiating treatment, confirm the diagnosis with acetylcholine receptor (AChR) antibodies (positive in ~80% of generalized MG), followed by muscle-specific kinase (MuSK) antibodies if AChR-negative, and electrodiagnostic studies including repetitive nerve stimulation or single-fiber EMG. 1, 2

Essential Initial Workup

• AChR antibodies are the first-line test, with sensitivity of 80% in generalized MG but only 50% in purely ocular disease 2
• Anti-MuSK antibodies must be checked when AChR is negative, as one-third of seronegative patients are MuSK-positive 2
• Single-fiber EMG has >90% sensitivity and is the gold standard for ocular myasthenia 2
• CT chest with contrast after diagnosis to evaluate for thymoma (occurs in 10-20% of AChR-positive patients) 2
• Pulmonary function testing with negative inspiratory force and vital capacity to assess respiratory muscle involvement 3, 2
• CPK, aldolase, troponin, and ECG to rule out concurrent myositis or myocarditis 3, 2

Stepwise Treatment Algorithm

First-Line: Symptomatic Treatment

Start pyridostigmine at 30 mg orally three times daily and gradually titrate up to a maximum of 120 mg four times daily based on symptom response. 3, 1, 2, 4

• Pyridostigmine is FDA-approved for myasthenia gravis and works by inhibiting acetylcholinesterase 4, 5
• Approximately 50% of patients, particularly those with ocular symptoms, show minimal response to pyridostigmine alone and require escalation to immunosuppressive therapy 1, 2
• Critical caveat: Pyridostigmine may be ineffective or even harmful in MuSK-antibody positive patients 6, 7
• In MuSK-positive MG, pyridostigmine can exacerbate AChR loss and worsen neuromuscular transmission 6

Second-Line: Corticosteroids

For Grade 2 disease (mild generalized weakness interfering with daily activities), add prednisone 1-1.5 mg/kg orally daily, with 66-85% of patients showing positive response. 3, 1, 2

• Corticosteroids demonstrate superior efficacy compared to pyridostigmine's 50% response rate 2
• Taper based on symptom improvement 3
• May resume checkpoint inhibitors in Grade 2 patients only if symptoms completely resolve 3

Third-Line: Rapid Immunomodulation for Severe Disease

For Grade 3-4 disease (moderate to severe weakness, respiratory compromise, or bulbar symptoms), permanently discontinue any checkpoint inhibitors, admit to ICU if needed, and initiate IVIG 2 g/kg IV over 5 days (0.4 g/kg/day) or plasmapheresis for 3-5 days while continuing corticosteroids. 3, 2

• IVIG and plasmapheresis are fast-acting treatments for disease exacerbations 3, 8
• Plasma exchange may be the favorable option for life-threatening symptoms 3
• Continue daily neurologic evaluation and frequent pulmonary function assessment 3, 9

Fourth-Line: Long-Term Immunosuppression

Azathioprine can be used as third-line immunosuppressive therapy for moderate to severe disease requiring steroid-sparing agents. 1, 10

• Other options include cyclosporine, cyclophosphamide, methotrexate, mycophenolate mofetil, or tacrolimus 10
• Rituximab may be considered in refractory cases 10

Surgical Intervention: Thymectomy

Always perform thymectomy when thymoma is present; evaluate thymectomy in all appropriate AChR-positive patients as it may substantially reduce symptoms and provide long-term immunomodulation. 2, 10, 8

Novel Therapies for Refractory Disease

Efgartigimod alfa-fcab is FDA-approved specifically for AChR-positive patients who are refractory to conventional therapy. 2

• Complement blockade agents (eculizumab, ravulizumab, zilucoplan) and neonatal Fc receptor antagonists (efgartigimod, rozanolixizumab) represent new treatment strategies 5

Critical Medication Avoidance

Immediately review and discontinue medications that worsen myasthenia: β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics. 3, 1, 2, 9

• These medications can precipitate or worsen myasthenic crisis 9
• This is a common pitfall that can lead to rapid deterioration 2

Monitoring Strategy

For All Patients

• Check renal function (serum creatinine) prior to every dose if on checkpoint inhibitor therapy 3
• Regular pulmonary function assessment is crucial as 50-80% of patients with initial ocular symptoms develop generalized myasthenia within a few years 1, 2

For Grade 3-4 Patients

• Daily neurologic evaluation 3, 9
• Frequent pulmonary function testing with negative inspiratory force and vital capacity 3, 9
• ICU-level monitoring may be necessary for rapidly progressive symptoms or respiratory muscle weakness 2, 9

Special Considerations by Antibody Status

AChR-Positive Patients

• Respond well to pyridostigmine, corticosteroids, and standard immunosuppression 2, 7
• Thymectomy should be strongly considered 2
• Efgartigimod is an option for refractory cases 2

MuSK-Positive Patients

• Generally do not respond to pyridostigmine and may worsen with its use 6, 7
• Require earlier escalation to immunosuppressive therapy 7
• Consider alternative symptomatic treatments like 3,4-diaminopyridine, which does not exacerbate AChR loss 6

Management of Ocular Myasthenia

• Start with pyridostigmine, but recognize that 50% show minimal response 1, 2
• Escalate to corticosteroids early when ocular motility abnormalities persist despite pyridostigmine 2
• Ice pack test (apply ice over closed eyes for 2 minutes) is highly specific for diagnosis and can temporarily reduce symptoms 1, 2
• Delay strabismus surgery until disease stabilization, typically requiring 2-3 years of medical treatment 2
• Requires collaboration between experienced ophthalmologist and neurologist 1, 2

Myasthenic Crisis Recognition and Management

Clinical Presentation

• Dysarthria, dysphagia, facial weakness, severe proximal muscle weakness, neck weakness preventing head support 9
• Fatigability with symptoms worsening with continued activity 9
• Bilateral but potentially asymmetric presentation 9

Immediate Management

• Admit to ICU with continuous monitoring 3, 2
• Quantify respiratory compromise with pulmonary function testing 9
• Initiate IVIG or plasmapheresis immediately while continuing corticosteroids 3
• Pyridostigmine may be discontinued or withheld in intubated patients 3
• Monitor for autonomic dysfunction, infections, delirium, and aspiration pneumonia 9