What is the pathophysiology of myasthenia gravis?

Pathophysiology of Myasthenia Gravis

Myasthenia gravis is an autoimmune disorder characterized by antibodies targeting components of the neuromuscular junction, primarily the acetylcholine receptor, leading to impaired neuromuscular transmission and resulting in fatigable muscle weakness. 1

Autoimmune Mechanism

• Primary Autoantibody Targets:

  • Acetylcholine receptor (AChR) antibodies: Present in approximately 85% of patients 2
  • Muscle-specific kinase (MuSK) antibodies: Present in about 6% of patients 2
  • Low-density lipoprotein receptor-related protein 4 (LRP4) antibodies: Found in some previously seronegative patients 2, 3

• Neuromuscular Junction Disruption:

  1. Acetylcholine is normally released at the neuromuscular junction when an action potential arrives
  2. It crosses the synapse to reach acetylcholine receptors on the muscle membrane
  3. In myasthenia gravis, autoantibodies interfere with this process through several mechanisms 1

Specific Pathophysiologic Mechanisms

• AChR Antibody Effects:

  • Decrease the number of functional acetylcholine receptors
  • Cause structural alterations to the postjunctional membrane
  • Result in neuromuscular transmission failure 4

• Extraocular Muscle Vulnerability:

  • Twitch fibers in extraocular muscles are particularly susceptible to fatigue
  • Fewer acetylcholine receptors in these muscles may explain the common ocular manifestations 1

• Role of the Thymus:

  • Thymic abnormalities present in many patients (thymoma in ~20% of cases) 3
  • Thymectomy can substantially reduce clinical symptoms in specific patient groups 1

Clinical Manifestations Related to Pathophysiology

• Fatigable Weakness Pattern:

  • Typically affects ocular, facial, bulbar, neck, and limb muscles
  • Worsens with repetitive use and improves with rest 1

• Variable Presentation:

  • Ocular symptoms (ptosis, diplopia) are initial presentation in 50% of patients
  • Progresses to generalized weakness in 50-80% of these patients within a few years 1
  • Can mimic various types of incomitant strabismus with or without ptosis 1

Diagnostic Implications of Pathophysiology

• Antibody Testing:

  • Detection of AChR antibodies (positive in ~85% of patients)
  • MuSK antibodies (positive in ~6% of patients)
  • LRP4 and other antibodies in previously seronegative cases 2, 3

• Electrophysiological Testing:

  • Demonstrates decremental response to repetitive nerve stimulation
  • Reflects the failure of neuromuscular transmission 3

Emerging Understanding

• Additional Antibody Targets:

  • Antibodies against titin, ryanodine receptor, agrin, collagen Q, Kv1.4 potassium channels, and cortactin have been identified in some patients 2
  • These can serve as useful biomarkers for disease subtyping

• Therapeutic Implications:

  • Understanding specific autoantibody profiles allows for targeted treatment approaches
  • Novel targeted therapies including B-cell targeted therapy, complement inhibitors, and FcRn inhibitors are being developed based on pathophysiologic mechanisms 5

Clinical Pearls Related to Pathophysiology

• The characteristic fatigability of muscles directly relates to the progressive depletion of functional acetylcholine receptors during repeated use
• The common early involvement of ocular muscles is explained by their particular vulnerability to neuromuscular transmission defects
• The variable presentation and course of the disease reflects differences in antibody targets, titers, and affected muscle groups

Understanding the pathophysiology of myasthenia gravis is essential for accurate diagnosis, appropriate treatment selection, and development of novel targeted therapies that address the specific autoimmune mechanisms involved in this complex disorder.