myasthenia gravis

Etiology

• autoimmune disorder
  • association with autoimmune thyroid disease
• humoral &/or cell mediated activity against nicotinic acetylcholine receptors
  • checkpoint inhibitor therapy may exacerbate preexisting myastheia or rarely induce de novo myastheia gravis
• thymoma

Epidemiology

• occurs most common in women 20-30 years & men > age 50 years

Pathology

• 85-95% of patients have antibodies to motor endplate nicotinic receptors
• since disease occurs in adults, mature nicotinic receptors, especially nicotinic receptor epsilon implicated as antigenic target
• among patients with antibodies to nicotinic receptors, 50% have antibodies to muscle-specific tyrosine kinase receptors
• muscle-specific kinase Ab in 1/2 of patients seronegative for nicotinic receptor Ab
• fluoroquinolones may decrease transmission at the neuromuscular junction & exacerbate myasthenia gravis

Clinical manifestations

• voluntary muscle weakness
  • muscle weakness may initially be transitory
    • painless & generally without sensory loss
    • included dysphagia & dsypnea
  • exacerbated by:
    • continuous use (i.e. muscle weakness worsens with repetitive movement)
    • warmer environment
    • later in day
    • physiologic stress
    • psychosocial stress
  • order of muscle group involvement
    • ocular 90%
      • ptosis or diplopia (1st manifestation in most patients)
      • strabismus
      • pupils are normal*
    • bulbar 40%
    • neck
      • expecially weakness of cervical extension
      • sensation of heaviness of head
    • limb-girdle
    • distal extremities
• diplopia
• eating difficulties
  • jaw weakness while chewing
  • choking
  • fluid regurgitation through nose when swallowing
  • food in mouth after swallowing
• dysarthria
  • difficulty maintaining volume of voice
  • unintelligible speech after prolonged speaking
• normal deep tendon reflexes
• normal sensation

* distinguishes from botulism

Laboratory

• nicotinic acetylcholine receptor antibody
  • positive in 85-95% of generalized myasthenia
  • ocular myasthenia less sensitive
• antistriational antibody is present in most patients with associated thymoma
• anti-MUSK Ab - affects therapy
• autoantibodies to C terminal portion of AKAP12 (gravin)
• serum TSH may be elevated with autoimmune thyroid disease
• see ARUP consult

Diagnostic procedures

• edrophonium (tensilon test):
  • Adults & children > 75 pounds:
    • 2 mg of edrophonium IV over 15-30 seconds
      • positive test: increased muscle strength
      • negative test: 8 mg additional edrophonium IV; evaluate muscle strength again
  • decreased doses for infants & children < 75 pounds
  • false negative tests occur especially with ocular myasthenia
  • false positive tests have been reported
• electromyography
  • decremental response to repetitive stimulation seen with myasthenia
  • repetitive single fiber stimulation
  • need to specifically request repetitive stimulation protocol
• ice-pack test
  • sustained upward gaze can produce ptosis in patients with myasthenia gravis
  • placing an ice pack over an eye with unilateral ptosis diminishes ptosis in patients with myasthenia gravis*

* acetylcholinesterase activity is inhibited at a lower temperature

Radiology

• CT of thorax to rule out thymoma

Complications

• respiratory failure (myasthenic crisis)
  • risk increased by:
    • surgical procedures
    • infections
    • corticosteroid therapy
    • use of aminoglycosides, quinolones
    • beta-blockers, calcium channel blockers

Differential diagnosis

• Eaton-Lambert syndrome
  • muscle weakness improves with repetitive movement
• botulism:
  • diplopia, dysphagia
  • sluggishly reactive or non-reactive pupils (normal in myasthenia gravis)
• muscular dystrophies
• brain tumors
• endocrine myopathies
• amyotrophic lateral sclerosis
• D-penicillamine administration may produce acetylcholine receptor Ab

Management

• early after onset of generalized myasthenia gravis
  • rituximab 500 mg single dose increases likelihood of minimal manifestations of myasthenia gravis & reduced need of rescue medications
• stop exacerbating factors:
  • over activity may exacerbate myasthenia
  • stress
    • physiologic - treat infections
    • psychosocial
  • medications
    • antibiotics: aminoglycosides, polymixins, tetracyclines, erythromycin
    • cardiac drugs: verapamil, beta blockers
    • phenytoin
    • chlorpromazine
• progressive respiratory failure (mysathenic crisis) with vital capacity < 15 mL/kg
  • endotracheal intubation
  • plasmapheresis or intravenous immunoglobulin
• pharmaceutical agents
  • acetylcholinesterase inhibitors
    • pyridostigmine (Mestinon) (treatment of choice)
      • can worsen respiratory secretions
      • avoid monotherapy with acute respiratory failure (myasthenic crisis)
    • neostigmine bromide (Prostigmin)
    • ambenonium chloride (Mytelase)
    • titrate to effect; diminish dose for drug adverse effects of cholinesterase inhibitors
  • immunosuppressive agents for more severe disease & ocular myasthenia
    • glucocorticoids (prednisone) can initially exacerbate myasthenia gravis
      • high dose IV methylprednisolone not beneficial for severe exacerbations or mysathenic crisis, but may worsen symptoms
    • cyclophosphamide (Cytoxan)
    • cyclosporin (Sandimmune)
    • rituximab
    • azathioprine (Imuran)
    • mycophenolate
      • similar efficacy to azathioprine but potentially fewer serious side effects
    • methotrexate may be tried when other immunosuppressants fail
  • plasmapheresis or intravenous immunoglobulin for more severe exacerbations or mysathenic crisis
  • complement C5 inhibitors
    • zilucoplan (Zilbrysq)
    • eculizumab may improve ~50% of refractory AChR-Ab + myasthenia
  • efgartigimod alfa-fcab (Vyvgart) FDA-approved
  • anti-MUSK Ab (antibodies to muscle-specific tyrosine kinase receptors
    • immunosuppression & IV IgG effective
    • rituximab is highly effective
  • fluoroquinolones may exacerbate myasthenia gravis
• sternal-splitting thymectomy
  • all patients with thymoma
  • need to minimize immunotherapy in patients without thymoma, active disease, + AChR-Ab, < 65 years, with 3 years of diagnosis
  • less effective with ocular myasthenia
  • not effective if anti-MUSK Ab
  • most effective if done early in the course of the disease
  • over 90% improve; many achieve clinical remission
• diet
  • calorie restriction
  • K+ supplementation may be necessary
• follow-up:
  • progression of weakness
  • thyroid function studies
  • screen for other autoimmune diseases

More general terms

• neuromuscular junction disorder
• autoimmune disease
• thymic disease

More specific terms

• familial myasthenia gravis

Additional terms

• acetylcholine (nicotinic) receptor antibody
• anti-striational antibody (anti-striated muscle antibody)
• Lambert-Eaton myasthenic syndrome (LEMS)
• myasthenic syndrome (congenital myasthenic syndrome, CMS)
• thymoma

Patient information

myasthenia gravis patient information

Database

• OMIM: https://mirror.omim.org/entry/254200