Myasthenia Gravis

Autoimmune disease of post-synaptic ACh receptors at the neuromuscular junction, leading to fatiguable weakness of skeletal and ocular muscles. Classified by the Osserman Classification:

Epidemiology and Risk Factors

  • Peak incidence in young adult women
    • Can occur at any age
    • Sex discrepancy differs over time
  • 8-10/1,000,000
  • No geographical variation
  • No racial variation

Pathophysiology

Disruption of muscle contraction by production of auto-antibodies to one of:

  • Nicotinic ACh receptor
    • Located at the post-synaptic cleft of the NMJ
    • Functionally antagonise ACh by blocking receptor binding
    • May also ↓ ACh receptor number via changing folding of synaptic cleft
    • Antibodies may have a thymic origin
      • Thymus hyperplasia in 70% of patients
      • Thymectomy
  • Muscle-specific Kinase
    • Results in ↓ number of ACh receptors
    • Causes seronegative MG

I have yet to find a satisfactory explanation for why this results in fatiguable weakness, rather than just weakness.

Aetiology

Clinical Manifestations

Fatiguable weakness of the:

Antibodies may be transferred across the placenta, so ~15% neonates from mothers with MG may demonstrate transient weakness.

  • Ocular muscles
    • Ptosis and diplopia most common initial symptoms
    • Usually asymmetrical
  • Limb and trunk weakness
    • Usually symmetrical

Diagnostic Approach and DDx

Investigations

Laboratory:

  • Blood
    • AChR antibodies
      Highly specific for ACh receptor mediated disease, but not other forms.

Other:

The Tensilon® (edrophonium chloride) test has been largely deprecated due to poor specificity, but is included for posterity. Process involves:

  • Have resuscitation facilities available
    Weakness and respiratory failure may result.
  • Atropine 0.6mg
    For muscarinic side effect prevention.
  • Edrophonium 1mg
    Acetylcholinesterase inhibitor.
  • Watch for improvement over 1-2 minutes
  • If no improvement, further 5mg of edrophonium
  • Electromyography
    • Repetitive nerve stimulation quantifies decreasing amplitude of response

Management

  • Anticholinesterases
  • Immunomodulation
    • Acute
    • Chronic

Specific therapy:

  • Pharmacological
    • Symptomatic treatment
      • Anticholinesterases
        • Pyridostigmine
          • Onset within 15-30 minutes, with duration of 3-4 hours
          • Usually commenced at 30mg PO QID, and then titrated to effect
            May be given IV, with 1mg IV ≃ 30mg PO.
    • Chronic immunomodulation
      • Corticosteroids
        May worsen symptoms in initial period.
        • 50-100mg/day prednisolone initially
        • 10-40mg/day for maintenance
      • Other immunosuppressants
        • Azathioprine
        • Mycophenolate
        • Ciclosporin
        • Tacrolimus
        • Rituximab
    • Acute immunomodulation
      • Plasmapheresis
        • 5 exchanges of 3-4 L over 2 weeks
        • Benefits last weeks
      • IVIG
        • 1-2g/kg over 1-2 days
        • Occasional long term benefit
  • Procedural
    • Thymectomy
      • Recommended for patients with thymic hyperplasia/thymoma
      • Usually early onset MG
  • Physical

Marginal and Ineffective Therapies

Anaesthetic Considerations

  • Perform elective surgery at a time of relative stability, when the patient requires minimal immunomodulation or glucocorticoids
  • Surgery should occur in the morning
    Usually greatest muscular strength.
  • Continue anticholinesterases
  • Stress dose steroids may be required
  • Consider ICU admission post-operatively
  • A
    • Bulbar symptoms
      Indicate risk of aspiration.
  • B
    • Respiratory muscle function
      Consider PFTs to predict need for ICU admission.
  • D
    • Conduct of anaesthesia
      Use short-acting agents to minimise respiratory depression and time taken for emergence.
  • E
    • Muscle relaxants
      Avoid wherever possible.
      • Highly sensitive to non-depolarising agents
      • Avoid reversal with neostigmine where possible
        May precipitate cholinergic crisis.
      • Resistant to suxamethonium

Inability to count to 10 in a single breath suggests an FEV1 <1L, and need for intubation.

Complications

Myasthenic Crisis

Sudden weakness of respiratory or bulbar muscles be precipitated by physiological stress, including:

Myasthenic crisis is much more common than cholinergic crisis.

  • Infection
  • Medication adjustment
    • Antibiotics
    • Antiarrhythmics
    • Local or general anaesthetics
    • Muscle relaxants
  • Surgery
  • Pregnancy

Management:

  • Neurologist involvement
  • Aggressive acute immunotherapy
    • ICU
    • Plasmapheresis
    • IVIG
  • May require intubation for aspiration prevention

Cholinergic Crisis

Sudden weakness due to excess ACh due to cholinesterase inhibition. Results in:

  • Weakness
  • Muscarinic/parasympathetic overactivity, i.e.
    • Salivation
    • Lacrimation
    • Urination
    • Defecation
    • Emesis

Prognosis

Key Studies

References

  1. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.