Myasthenia Gravis

• MG is an autoimmune neuromuscular disorder that is characterised by weakness and fatigue
• MG is due to antibody-mediated blockage of neuromuscular transmission, predominantly due to the formation of acetylcholine receptor antibodies (AChR-Ab)

  Bind to acetylcholine receptors at the neuromuscular junction
• The hallmark of MG is fatiguability, which refers to increasing muscle weakness with repeated use.
• MG can occur at any age and it has a bimodal peak in incidence:

  • 2nd-3rd decade of life: predominantly females
  • 6th-7th decade of life: predominantly males
• In MG, 10-15% of patients have a thymoma (rare benign tumour of thymus gland) and up to 85% have thymic hyperplasia. The disease may even improve or regress with removal of the thymus gland.
• The thymus is a bilobed lymphoid organ important in the development of T lymphocytes (i.e. T cells), which is situated in the anterior superior mediastinum of the thorax. 
• MG is associated with other autoimmune diseases including Graves’ disease, systemic lupus erythematous, and rheumatoid arthritis, among others.
• Clinical subtypes of MG:

  • Ocular MG - weakness limited to eyelids extraocular muscles
  • Generalised MG - can affect numerous muscle groups including neck, bulbar, limbs, respiratory and ocular
• Antibody subtypes:

  • MG with AChR-Ab (80-90% of cases)
  • MG with anti-MuSK
  • MG with anti-LRP4
• The hallmark clinical feature of MG, in both ocular and generalised, is fluctuating skeletal muscle weakness. This usually presents with fatiguability that refers to increased muscle weakness on repeated use.
• Symptoms are commonly worse at the end of the day or following exercise. As the condition progresses, there may be no periods of normal muscle function. Instead, weakness may merely fluctuate between mild and severe.
• Ocular symptoms:

  • More than 50% present with ocular symptoms
  • Diplopia - Should improve on closing one eye
  • Ptosis
  • Weak eye muscles/ ophthalmoplegia
  • Pupillary sparing
• Generalised symptoms:

  • Bulbar muscles - fatigued chewing, dysarthria, dysphagia
  • Facial muscles - expressionless face. Poor smile or classical myasthenic sneer - mid lip rises but outer mouth corners fail to move
  • Neck muscles - may get dropped head syndrome towards the end of the day
  • Limb muscles - mainly proximal muscle weakness. Arms affected more than legs.
  • Respiratory muscles
• Ice pack test:

  • Refers to the improvement of ptosis in patients with MG after the application of a bag filled with ice to the closed eyelid for one minute. After removal, the extent of ptosis is immediately assessed. There should be a short duration of improvement (< 1 minute). Sensitivity is approximately 80%.
  • Neuromuscular transmission is better at lower muscle temperature
• Bedside tests:

  • Ice-pack test: discussed above
  • Edrophonium (tensilon) test: no longer completed in clinical practice. Consisted of an infusion of edrophonium, which is an acetylcholinesterase inhibitor with rapid onset and short duration. Leads to a brief improvement in symptoms in patients with obvious ptosis or ophthalmoplegia. False positive and negatives. Safety concerns due to muscarinic side-effects (e.g. bradycardia, bronchospasm).
• Serological tests:

  • AChR-Ab: 90% of generalised, 50% of ocular MG. High specificity (~99%). Rarely, may see false positives in a patient with thymoma without MG. 
  • MuSK and LRP4: completed if AChR-Abs are negative. Typical clinical phenotype. 
  • Others: multiple antibodies against differentiate components of skeletal muscle (Anti-striated muscle antibodies). Strongly linked with thymoma.
• Neurophysiology tests:

  • Repetitive nerve stimulation (RNS) and electromyography (EMG) can be used to help diagnose MG, especially in seronegative cases. 
  • In MG, with repeated stimulation there is a progressive decline in amplitude suggesting fatiguability.
• All patients with suspected MG, irrespective of clinical or serological subtype need to undergo assessment of the thymus gland using CT or MRI. 
• All patients should undergo thyroid function tests because of the strong association with thyroid autoimmune disease. Other tests including a rheumatological screen (e.g. ANA, ENA, CCP, RF) or cerebral imaging (e.g. MRI brain) are guided by the clinical presentation and presence or absence of typical antibodies.
• The principle initial treatment for MG is pyridostigmine, which is an acetylcholinesterase inhibitor.
• Treatment options:

  • First line - Acetylcholinesterase inhibitors e.g. pyridostigmine - prevent the hydrolysis of acetylcholine and increases its effect at the NMJ.
  • Corticosteroids - alternate day strategy
  • Immunosuppressants - usually azathioprine
• Acetylcholinesterase inhibitors (e.g. pyridostigmine) - Associated with cholinergic side-effects (secretions, diarrhoea, GI upset, bronchospasm, sweating, urinary incontinence).
• Myasthenic crisis is a life-threatening condition - worsening of weakness that requires respiratory support

  • Significant bulbar symptoms
  • Low FVC
  • Respiratory symptoms
  • Progressive deterioration
• Patients with, or at risk of a myasthenic crisis should be treated with urgent IVIG, corticosteroids and consider plasma exchange
• Pyridostigmine should generally be avoided during an acute crisis due to the increase in respiratory secretions and risk of aspiration.