Myasthenia Gravis (MG)

Severe autoimmune neuromuscular disorder characterised by severe muscular weakness and progressive fatigue

Aetiology

  • Autoimmune
    • Also associated with other autoimmune disorders such as SLE, rheumatoid arthritis, and thyrotoxicosis
  • 90% - no known cause
    • Genetic predisposing factor - HLA associations
  • Thymic tumour - 10%
  • Can occur at any age but usually presents at after middle age - most commonly 60-70
  • May first appear during pregnancy, postpartum or with the administration of certain anaethetic agent

Pathophysiology

  • Autoimmune disease in which auto-reactive antibodies (auto-IgG) bind with postsynaptic ACh receptors on muscle cells - type II hypersensitivity
  • Involvement of CD4+ TH cells and AChR self-antigens in activating auto-reactive B cells

Thymus involvement

  1. CD4+ TH cells are activated by unfolded AChR subunits expressed by thymic epithelial cells
  1. Cde4+ TH cells stimulate auto-reactive B cells, resulting in the production of anti-AChR IgG auto-antibodies
  1. Thymic myoid cells that express intact AChRs are then attacked by these antibodies, and then release AChR-immune complexes
  1. AChR-immune complexes in turn activate antigen presenting cells and diversify the autoantibody response to recognise intact AChRs of normal muscle cells
  1. AChR auto-antiodies block binding of endogenous ACh ligands to these receptors
  1. Eventually, AChRs are destroyed:
    1. Antibody-bound receptors are internalised and degraded
    2. ACHR antibodies bound to Complement (membrane attack complex), leading to descruction of the muscle endplate
  1. The number of functional channels in the endplate are reduced → amplitude of endplate potential decreases → impaired signal conduction at the NMJ

Clinical presentation

  • Onset typically insidius
  • Initial symptoms involve ocular muscles in 60% of cases
  • Complaints are fatigue and progressive muscle weakness
    • Muscles of the eyes, face, mouth, throat and neck are usually affected first
    • Less frequenctly involved are the muscles of the neck, shoulder girdle and hip flexors
    • In advanced stage all muscles are weak → life-threatening impairment of respiration

Investigations

  • Lab tests - anti-AChR IgG in serum
  • Repetitive nerve stimulation - gradually reducing responses indicates NMJ dysfunction

Management

  • Increase neurotransmission (first line) - anticholinesterases (e.g. pyridostigmine)
    • Increase the concentration of ACh in the synaptic cleft
  • Reduce autoimmune reactions (second line) - immunosuppressive drugs, corticosteriods
  • Surgery - thymectomy if MG is associated with thymic tumour (first line if indicated)