What is Myasthenia Gravis?

Myasthenia Gravis: An Autoimmune Neuromuscular Junction Disorder

Myasthenia gravis is an autoimmune disease characterized by variable muscle weakness and fatigue due to antibodies targeting components of the neuromuscular junction, primarily affecting the acetylcholine receptor pathway and resulting in impaired neuromuscular transmission. 1, 2

Definition and Pathophysiology

• Myasthenia gravis (MG) is a B-cell mediated autoimmune disorder that profoundly affects activity at the neuromuscular junction, causing variable weakness exacerbated by fatigue 1, 2
• The disease involves antibodies directed against components at the postsynaptic membrane of the neuromuscular junction:
  • Acetylcholine receptor antibodies (present in nearly all patients with generalized MG and 40-77% of ocular MG) 1
  • Muscle-specific kinase (MuSK) antibodies (in about one-third of seronegative patients) 1, 2
  • Lipoprotein-related protein 4 (LRP4) antibodies 1, 3
  • Agrin antibodies (emerging as a potential new entity) 2
• Twitch fibers in extraocular muscles are particularly susceptible to fatigue, explaining the common ocular manifestations 1

Epidemiology

• Incidence ranges from 0.04 to 5 per 100,000 per year 1
• Prevalence estimates are 0.5 to 12.5 per 100,000 per year 1
• Bimodal age distribution:
  • Peak onset in women during second and third decades of life 4
  • Peak onset in men during fifth and sixth decades 4
• Slight female preponderance with a sex ratio of 3:2 4

Clinical Presentation

• Ocular symptoms (present in 50% of patients at initial presentation):

  • Ptosis (drooping eyelids) that worsens with fatigue 1
  • Variable strabismus causing diplopia (double vision) 1
  • Cogan lid-twitch sign (brief overshoot of eyelid when looking from down to primary position) 1
  • Slow ocular saccades 1

• Generalized symptoms (develop in 50-80% of patients with initial ocular symptoms within a few years):

  • Bulbar symptoms: difficulty chewing, swallowing, speaking (dysarthria) 1
  • Limb weakness, typically proximal more than distal 1, 5
  • Neck muscle weakness 1
  • Respiratory muscle weakness (can lead to life-threatening respiratory failure) 1

• Key clinical characteristics:

  • Fluctuating weakness that worsens with activity and improves with rest 1, 5
  • Variable patterns of muscle involvement that can change during examination 1
  • No pupillary involvement in most cases (pupillary abnormalities should prompt consideration of other diagnoses) 1

Diagnosis

• Clinical evaluation:

  • Complete sensorimotor and external examination 1
  • Ice pack test: application of ice over closed eyes for 2-5 minutes may reduce ptosis and strabismus (highly specific for MG) 1
  • Rest test: improvement of symptoms after a period of rest 1

• Laboratory testing:

  • Acetylcholine receptor antibodies (AChR-Ab): present in nearly all generalized MG and 40-77% of ocular MG 1
  • Anti-MuSK antibodies: present in about one-third of seronegative patients 1, 2
  • Anti-LRP4 antibodies: emerging biomarker 1, 3

• Electrophysiological studies:

  • Repetitive nerve stimulation: positive in only one-third of ocular MG cases 1
  • Single-fiber electromyography: positive in over 90% of ocular MG cases (considered the gold standard in many centers) 1

• Pharmacological testing:

  • Tensilon (edrophonium) test: 95% sensitive for generalized MG and 86% sensitive for ocular MG 1
  • Caution: Must be performed in a monitored setting with atropine available due to risk of muscarinic side effects 1, 6

• Additional workup:

  • Chest imaging to evaluate for thymoma 1
  • Evaluation for associated autoimmune disorders, particularly thyroid disease 1

Management

• First-line treatment:

  • Pyridostigmine bromide (acetylcholinesterase inhibitor): administered orally 2-4 times daily 1, 2
  • Note: About half of patients with strabismus-associated myasthenia show minimal response to pyridostigmine 1

• Immunosuppressive therapy:

  • Corticosteroids: 66-85% of patients show positive response 1
  • Azathioprine: effective as a steroid-sparing agent 1, 2
  • Newer agents: efgartigimod alfa-fcab (FDA approved for anti-acetylcholine receptor positive patients) 1

• Surgical intervention:

  • Thymectomy: indicated in all cases of thymoma and in specific age-based and immune-based characteristics 1
  • Can substantially reduce symptoms in certain subpopulations 1

• Management of ocular symptoms:

  • Diplopia and strabismus are highly variable and often not readily remedied with prisms 1
  • Surgical intervention for strabismus may be considered after 2-3 years when disease has stabilized 1
  • Multiple strabismus surgeries may be necessary 1

Important Considerations and Pitfalls

• Myasthenic crisis vs. cholinergic crisis:

  • Myasthenic crisis: worsening weakness due to disease progression, requires increased anticholinesterase therapy 6
  • Cholinergic crisis: weakness due to overdose of anticholinesterase medications, requires immediate withdrawal of these drugs 6
  • Differentiation is critical as management is radically different 6

• Respiratory involvement:

  • Monitor for signs of respiratory compromise which can be life-threatening 1
  • Particular care needed with anesthetic agents in patients with respiratory muscle weakness 1

• Cardiac involvement:

  • Can range from asymptomatic ECG changes to conduction disorders, myocarditis, heart failure 4
  • Consider cardiac evaluation in patients with symptoms suggesting cardiovascular involvement 4

• Multidisciplinary approach:

  • Management typically requires collaboration between ophthalmologists, neurologists, and sometimes general surgeons 1
  • Regular monitoring for disease progression from ocular to generalized form is essential 1