What is the workup for myasthenia gravis (MG) diagnosis and management?

Workup for Myasthenia Gravis Diagnosis and Management

Diagnostic Workup

Begin with serological testing for anti-acetylcholine receptor (AChR) antibodies as the first-line diagnostic test, which confirms diagnosis in approximately 80% of generalized MG cases, followed by anti-muscle-specific kinase (MuSK) antibodies if AChR is negative, and electrodiagnostic studies with single-fiber EMG as the gold standard when antibodies are negative. 1, 2

Initial Serological Testing (in order of priority)

• Anti-AChR antibodies first: Present in ~80% of generalized MG but only 50% of purely ocular MG 1, 2
• Anti-MuSK antibodies: Test when AChR is negative, as approximately one-third of seronegative patients will be MuSK-positive 2
• Anti-striated muscle antibodies: Include in initial workup 1, 2

Electrodiagnostic Studies

• Single-fiber EMG (SFEMG): Gold standard with >90% sensitivity for ocular myasthenia 1, 2
• Repetitive nerve stimulation: Less sensitive (positive in only one-third of ocular cases) but more widely available 1, 2
• Standard EMG and nerve conduction studies: May be normal early in disease course; operator-dependent and require specialized expertise 1

Bedside Clinical Tests

• Ice pack test: Apply ice pack over closed eyes for 2 minutes and observe for symptom reduction—highly specific for MG, particularly ocular symptoms 1, 2, 3
• Edrophonium (Tensilon) test: 95% sensitivity for generalized MG and 86% for ocular MG, but requires experienced practitioners with atropine available due to muscarinic side effects 2

Essential Supplementary Workup After Diagnosis Confirmation

• CT chest with contrast: Evaluate for thymoma, which occurs in 10-20% of AChR-positive patients 2
• Pulmonary function testing: Measure negative inspiratory force (NIF) and vital capacity (VC) to assess respiratory muscle involvement 2
• Cardiac evaluation: CPK, troponin, and ECG; consider echocardiogram or cardiac MRI to rule out concomitant myocarditis 4, 2
• Inflammatory markers: CPK, aldolase, ESR, and CRP to evaluate for concurrent myositis 2
• Neurology consultation: Essential for all suspected cases 4, 1

Key Diagnostic Pitfalls to Avoid

• Pupillary involvement excludes MG: Pupils are characteristically not affected in MG; if pupils are abnormal, prioritize evaluation for third nerve palsy, Horner syndrome, or other neurologic causes 1
• Normal CSF: Helps distinguish MG from Guillain-Barré syndrome where CSF protein is often elevated 1
• Consider differential diagnoses: Third nerve palsy (pupillary abnormalities present), thyroid eye disease (proptosis, eyelid retraction, tendon-sparing muscle enlargement on imaging), chronic progressive external ophthalmoplegia, Lambert-Eaton syndrome, botulism, and brainstem lesions 1

Management Algorithm

Step 1: Symptomatic Treatment (All Patients)

Start pyridostigmine at 30 mg orally three times daily and gradually increase to maximum 120 mg four times daily based on symptoms and tolerability. 1, 2, 3

• Approximately 50% of patients, particularly those with ocular manifestations, show minimal response to pyridostigmine alone and require escalation 1, 2, 3
• Monitor for cholinergic crisis: increasing muscle weakness, respiratory muscle involvement, gastrointestinal symptoms 5
• Critical warning: Overdosage can result in cholinergic crisis characterized by increasing muscle weakness leading to respiratory failure; differentiate from myasthenic crisis using edrophonium chloride and clinical judgment 5

Step 2: Immunosuppressive Therapy (Grade 2 Disease or Inadequate Response to Pyridostigmine)

Add prednisone 0.5-1.5 mg/kg orally daily for Grade 2 disease (mild generalized weakness, symptoms interfering with activities of daily living), as corticosteroids demonstrate superior efficacy with 66-85% positive response rates compared to pyridostigmine's 50% response rate. 1, 2

• Wean based on symptom improvement 4
• Corticosteroids are the most consistently effective immunosuppressive agents but carry the highest incidence of potential side effects 2

Step 3: Acute/Severe Treatment (Grade 3-4 Disease)

For moderate to severe weakness (Grade 3-4), add IVIG 2 g/kg IV over 5 days (0.4 g/kg/day) or plasmapheresis for 3-5 days plus concurrent corticosteroids (methylprednisolone 2-4 mg/kg/day). 4, 2

• Permanently discontinue immune checkpoint inhibitors if MG is ICPi-related 4
• Admit patient with ICU-level monitoring capability 4, 2
• Daily neurologic evaluation and frequent pulmonary function assessment 4, 2

Step 4: Steroid-Sparing Immunosuppressants (Third-Line)

Azathioprine can be used as third-line immunosuppressive therapy for moderate to severe disease or as a steroid-sparing agent. 1, 2

• Alternative options include mycophenolate mofetil and tacrolimus 6

Step 5: Surgical Intervention

Evaluate for thymectomy in appropriate AChR-positive patients, as it may substantially reduce symptoms and increase remission rate. 2, 6

• Always perform thymectomy when thymoma is present 2
• International multicenter randomized trial demonstrated thymectomy plus prednisone improves clinical outcomes compared to prednisone alone in selected nonthymomatous MG patients 6
• Critical preoperative consideration: Any patient with suspected MG requiring surgery must have serum anti-AChR antibody levels measured preoperatively to avoid respiratory failure during anesthesia 1

Step 6: Novel Biologics (Refractory Disease)

For AChR-positive patients refractory to conventional therapy, consider FDA-approved biologics including efgartigimod alfa-fcab, eculizumab, or ravulizumab. 2, 6

• Rituximab is a good option especially for MuSK-positive patients 6

Critical Medication Avoidance

Immediately review and discontinue medications that worsen myasthenia: β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics. 4, 1, 2

Monitoring Requirements

Ongoing Assessment

• Regular pulmonary function monitoring: Crucial as 50-80% of patients with initial ocular symptoms develop generalized myasthenia within a few years 1, 2, 3
• Daily neurologic evaluation: For Grade 3-4 patients 4, 2
• Monitor for autonomic dysfunction: Particularly in severe cases 4

Ocular-Specific Management

• Ocular symptoms are highly variable and not readily remedied with prisms 2, 3
• Strabismus surgery should only be considered after disease stabilization, typically requiring 2-3 years of medical treatment 2, 3
• Management requires collaboration between experienced ophthalmologist and neurologist 1, 2

Treatment Response by Antibody Subtype

• AChR-positive: Best response to thymectomy and conventional immunosuppression 2, 6
• MuSK-positive: Consider rituximab as preferred biologic 6
• Seronegative: May have antibodies to lipoprotein-related protein 4; treatment responses may differ based on disease subtypes 6