What are the steps involved in the clinical diagnosis and treatment of myasthenia gravis?

Clinical Diagnosis and Treatment of Myasthenia Gravis

The diagnosis of myasthenia gravis requires a comprehensive diagnostic workup including antibody testing, electrodiagnostic studies, and specialized bedside tests, followed by a stepwise treatment approach starting with pyridostigmine and escalating to immunosuppressive therapy based on disease severity.

Diagnostic Approach

Clinical Presentation

• Variable incomitant strabismus often accompanied by variable ptosis
• Symptoms worsen with fatigue and improve with rest
• Possible diplopia, dysarthria, dysphagia, and limb weakness
• Ocular symptoms (ptosis, diplopia) may progress to generalized weakness in 50-80% of patients 1

Diagnostic Testing Algorithm

1. Bedside Tests:

   • Ice Test: Apply ice pack over closed eyes for 2 minutes (ptosis) or 5 minutes (strabismus)
     • Positive result: Reduction of ptosis by ~2mm or reduction in misalignment
     • Highly specific for myasthenia gravis 1, 2
   • Rest Test: Observe for improvement after period of rest 1

2. Serological Testing:

   • Acetylcholine receptor antibodies (AChR) - first-line test
   • If AChR negative, test for:
     • Muscle-specific kinase (MuSK) antibodies
     • Lipoprotein-related protein 4 (LRP4) antibodies 1
   • Note: About 50% of ocular myasthenia and 20% of generalized myasthenia patients are seronegative 1

3. Electrodiagnostic Studies:

   • Single-fiber electromyography (SFEMG): Gold standard with >90% sensitivity for ocular myasthenia 1, 3
   • Repetitive nerve stimulation: Shows decremental response, positive in only one-third of ocular myasthenia cases 1

4. Pharmacologic Testing:

   • Edrophonium (Tensilon) test:
     • Adult dosing: 2 mg IV initially, followed by 8 mg if no response after 45 seconds
     • Must be performed in monitored setting with atropine available
     • 95% sensitive for generalized myasthenia, 86% for ocular myasthenia 1, 4

5. Additional Testing:

   • Pulmonary function assessment: Negative inspiratory force and vital capacity
   • Laboratory studies: CPK, aldolase, ESR, CRP (to evaluate for concurrent myositis)
   • Cardiac evaluation: ECG and echocardiogram if respiratory symptoms or elevated CPK/troponin 1
   • Imaging: MRI brain/spine to rule out other diagnoses 1

Treatment Algorithm

First-Line Treatment

• Pyridostigmine bromide (Mestinon):
  • Starting dose: 30 mg PO three times daily
  • Gradually increase to maximum of 120 mg four times daily based on symptoms
  • Note: Only about 50% of patients with strabismus-associated myasthenia show adequate response 1, 5

Second-Line Treatment

• Corticosteroids:
  • Prednisone 1-1.5 mg/kg PO daily
  • 66-85% of patients show positive response 1
  • Gradually taper based on symptom improvement

Treatment Based on Severity

Grade 2 (Mild Generalized Weakness)

• Continue pyridostigmine
• Add corticosteroids if symptoms persist
• Neurology consultation 1

Grade 3-4 (Moderate to Severe Weakness)

• Hospital admission (may require ICU monitoring)
• Continue corticosteroids
• Add IVIG (2 g/kg over 5 days) or plasmapheresis for 5 days
• Daily neurologic evaluation
• Frequent pulmonary function assessment 1

Additional Treatment Options

• Immunosuppressive therapy:
  • Azathioprine (effective steroid-sparing agent)
  • Newer agents like efgartigimod alfa-fcab (FDA approved for AChR-positive patients) 1
• Thymectomy:
  • Always indicated if thymoma present
  • May substantially reduce symptoms in certain subpopulations 1
• Surgical management for strabismus:
  • Consider only after disease stabilization (typically 2-3 years after treatment)
  • May require adjustable sutures and multiple procedures 1

Important Clinical Considerations

Myasthenic vs. Cholinergic Crisis

• Myasthenic crisis: Worsening weakness due to disease progression - requires increased anticholinesterase therapy
• Cholinergic crisis: Weakness due to medication overdose - requires immediate withdrawal of anticholinesterase drugs and atropine administration 5
• Differentiation may require edrophonium testing and careful clinical judgment

Medications to Avoid

• β-blockers
• IV magnesium
• Fluoroquinolones
• Aminoglycosides
• Macrolides 1

Multidisciplinary Approach

• Coordination between ophthalmologist, neurologist/neuro-ophthalmologist, and sometimes general surgeon is essential for optimal management 1
• Regular monitoring for respiratory compromise is crucial, as this can lead to mortality if untreated

Long-term Outlook

• Ocular myasthenia may progress to generalized disease in 50-80% of patients
• ICPi-associated myasthenia gravis may be monophasic and not require long-term immunosuppression 1
• Remission or stabilization often possible after 2-3 years of treatment 1

By following this systematic approach to diagnosis and treatment, clinicians can effectively manage myasthenia gravis and minimize its impact on morbidity, mortality, and quality of life.