What is the recommended step‑by‑step management of an adult with generalized myasthenia gravis, including acetylcholinesterase inhibitor therapy, corticosteroids, steroid‑sparing immunosuppressants, thymectomy, and rescue treatment for myasthenic crisis?

Management of Generalized Myasthenia Gravis in Adults

Initial Symptomatic Treatment with Acetylcholinesterase Inhibitors

Begin pyridostigmine at 30 mg orally three times daily and titrate upward based on clinical response to a maximum of 120 mg orally four times daily. 1

• Pyridostigmine provides symptomatic relief by increasing acetylcholine availability at the neuromuscular junction but does not modify the underlying autoimmune process. 2
• Instruct patients to take medication exactly as prescribed and plan activities around peak medication effect for optimal strength. 1
• Approximately 50% of patients with ocular myasthenia show minimal response to pyridostigmine alone, and many patients with generalized disease require escalation to immunosuppressive therapy. 1, 2

Corticosteroid Therapy for Inadequate Response

For Grade 2 symptoms (mild generalized weakness interfering with activities of daily living), add prednisone 1–1.5 mg/kg orally daily if pyridostigmine provides insufficient control. 1

• Corticosteroids are the most effective first-line immunosuppressive agent, with 66–85% of patients showing positive response. 2
• Expect sustained improvement within the first two weeks, reaching maximal improvement at approximately three months. 3
• Critical pitfall: Exacerbations of myasthenic weakness may occur in the early phases of corticosteroid treatment, typically with mean onset at 5 days and mean duration of 6 days; most exacerbations are mild but patients must be warned and monitored closely. 3
• Taper corticosteroids gradually based on symptom improvement, transitioning to alternate-day maintenance therapy at the lowest dose that maintains maximal improvement. 1, 3

Steroid-Sparing Immunosuppressants

Azathioprine is the first-choice steroid-sparing immunosuppressant for patients requiring prolonged immunosuppression or those unable to tolerate corticosteroid side effects. 4

• Azathioprine allows reduction of corticosteroid dose and is effective across all clinical forms of myasthenia gravis. 4
• Mycophenolate mofetil and cyclosporine serve as second-choice agents when azathioprine is not tolerated or ineffective. 4
• Overall, 82% of patients with generalized myasthenia gravis require immunosuppressants for at least 1 year, with rates varying by disease severity. 4
• The rate of remission or minimal manifestations ranges from 85% in ocular myasthenia to 47% in thymoma-associated disease with immunosuppressive therapy. 4

Thymectomy Indications and Timing

Following establishment of maximal improvement on corticosteroids (approximately 3 months), consider thymectomy for anti-acetylcholine receptor antibody-positive patients, particularly those with early-onset myasthenia gravis (age <50 years). 3, 5, 6

Patient Selection for Thymectomy

• Thymectomy is most beneficial in early-onset myasthenia gravis (EOMG), where Complete Stable Remission is achieved significantly more frequently than in late-onset or thymoma-associated disease. 5
• Patients with late-onset myasthenia gravis (LOMG, age >50 years) and thymoma-associated myasthenia gravis also respond to thymectomy, but therapy success is less pronounced and delayed compared to EOMG. 5
• The sternum-splitting procedure is tolerated extremely well by patients exhibiting marked improvement or remission while on corticosteroids. 3
• Minimally invasive approaches (extended robotic thymectomy) lead to similar positive outcomes as transsternal approach with potentially fewer short-term adverse effects. 6

Post-Thymectomy Management

• Continue maintenance corticosteroid therapy following surgery; consider attempting to discontinue steroids at approximately one year post-thymectomy. 3
• If relapse occurs after steroid discontinuation, reinitiate oral corticosteroid treatment. 3
• Treatment can ultimately be withdrawn in nearly 20% of anti-AChR positive early-onset patients, but in only 7% of thymoma cases. 4
• Long-term follow-up confirms that benefits regarding clinical outcomes and reduced need for immunosuppressive treatment persist after thymectomy. 6

Rescue Treatment for Myasthenic Crisis (Grade 3–4)

For myasthenic crisis with respiratory compromise or severe generalized weakness, immediately hospitalize with ICU-level monitoring and initiate IVIG 2 g/kg total dose over 5 days (0.4 g/kg/day × 5 days) or plasmapheresis. 1

Acute Crisis Management Algorithm

• Immediate actions: Permanently discontinue any causative immune checkpoint inhibitors, admit to ICU with respiratory monitoring capability, and obtain urgent neurology consultation. 1
• Continue high-dose corticosteroids concurrently during IVIG or plasmapheresis treatment. 1
• Perform frequent pulmonary function assessments with negative inspiratory force (NIF) and vital capacity (VC) monitoring. 1
• Pyridostigmine may be continued during IVIG or plasmapheresis but should be discontinued or withheld if intubation is required. 1
• Critical pitfall: Sequential therapy (plasmapheresis followed by IVIG) is no more effective than either treatment alone and should be avoided. 1

IVIG vs. Plasmapheresis Selection

• IVIG is specifically preferred in pregnant women due to easier administration and fewer complications. 1
• In resource-limited settings, plasmapheresis may be more cost-effective than IVIG, though this advantage is offset by the need for specialized equipment and trained personnel. 1
• Both therapies carry comparable overall risks, though early studies demonstrated plasmapheresis was more likely to be discontinued due to adverse events. 1

Weaning from Mechanical Ventilation

• Measure NIF and VC frequently during the weaning phase; NIF values improving toward normal ranges (more negative than -30 cmH₂O) indicate adequate respiratory muscle strength for spontaneous breathing. 7
• Do not attempt extubation if bulbar symptoms persist (dysphagia, facial weakness), as these indicate inadequate airway protection and high reintubation risk. 7
• Reintroduce pyridostigmine during the weaning phase when the patient begins resuming spontaneous breathing efforts, starting at 30 mg orally three times daily. 7

Critical Medications to Avoid

Educate patients to strictly avoid medications that worsen myasthenic symptoms, as these can precipitate myasthenic crisis. 1

• β-blockers (interfere with neuromuscular transmission) 1
• Intravenous magnesium (blocks acetylcholine release) 1
• Fluoroquinolone antibiotics (e.g., ciprofloxacin, levofloxacin) 1
• Aminoglycoside antibiotics (e.g., gentamicin, tobramycin) 1
• Macrolide antibiotics (e.g., azithromycin, erythromycin) 1
• Metoclopramide should not be given to patients with myasthenia gravis, as it can trigger myasthenic crisis. 1

Monitoring and Warning Signs

Teach patients to monitor for and immediately report worsening symptoms, particularly dysphagia, as oropharyngeal and bulbar weakness are present in more than 50% of cases that precede myasthenic crisis. 1, 2

• Changes in speech or swallowing (bulbar symptoms) are critical warning signs requiring urgent evaluation. 1
• Respiratory difficulties, including shortness of breath with light activity, warrant immediate pulmonary function assessment. 1
• Double vision (diplopia) and increased ptosis indicate disease progression. 1
• Regular pulmonary function assessment is crucial for patients with generalized myasthenia gravis to monitor for respiratory compromise. 2

Diagnostic Confirmation Requirements

Confirm diagnosis with acetylcholine receptor (AChR) antibodies and antistriated muscle antibodies; if AChR negative, test for muscle-specific kinase (MuSK) and lipoprotein-related protein 4 (LRP4) antibodies. 1

• Approximately 50% of individuals with purely ocular myasthenia gravis are seronegative for AChR antibodies; negative AChR does not exclude diagnosis. 2
• Single-fiber electromyography has sensitivity >90% for myasthenia gravis and is the gold-standard electrodiagnostic test. 2
• The ice-pack test (applying ice over closed eyes for 2 minutes) is highly specific for myasthenia gravis, particularly for ocular symptoms. 2