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myasthenia%20gravis
MYASTHENIA GRAVIS
Myasthenia gravis is an autoimmune neurological disorder caused by autoantibodies against the acetylcholine receptor or against a receptor-associated protein, muscle-specific tyrosine kinase (MuSK-Ab).
The autoimmune attack at the muscle endplate leads to failure of neuromuscular transmission and eventually muscle weakness.
In the active phase of the disease, symptoms typically fluctuates and then become severe; myasthenic crisis occur in this phase.
In the stable/inactive phase, symptoms are stable but still persist; it usually worsen attributable to infection, fatigue, tapering of medications or other identifiable factors.
In the burnt-out phase, remission may occur wherein patients are on immunotherapy and symptom-free, or may even be off medications.
In 15-20 years, if the symptoms left untreated, patient's weakness becomes fixed wherein the most severely affected muscles become atrophic.

Myasthenia%20gravis Treatment

Pharmacotherapy

Anticholinesterase Agents

  • 1st-line therapy for all forms of myasthenia gravis
  • Patients usually experience partial improvement; complete improvement occurs in few patients
    • No difference in efficacy between different anticholinesterase agents
    • Does not stop natural progression of disease state
  • Dose & frequency should be tailored to patient’s individual needs
  • Muscarinic side effects (eg diarrhea, abdominal cramps, etc) may limit tolerated dose
    • Propantheline may be used to block unwanted autonomic side effects
    • Loperamide may be used to treat diarrhea

Distigmine

  • Longer-acting, but rarely used for MG because of the increased risk of cholinergic crisis

Neostigmine

  • An analog of Pyridostigmine with therapeutic effect at approx 4 hours
  • Shorter action & is less effective; with more muscarinic side effects

Pyridostigmine

  • Most commonly used anticholinesterase agent
    • May be used as long-term treatment in patients with milder disease
  • Effect begins within 30 minutes, peaks at about 2 hours & lasts for 3-4 hours
  • May be preferable to Neostigmine because of its smoother action & less frequent dosing
    • Not as powerful & slower in onset of action, but it does have a longer duration of action than Neostigmine
Corticosteroid

Prednisolone (Prednisone)

  • Generally produces improvement of weakness in myasthenia gravis patients
    • Based on observational studies, remission or marked improvement occurs in 70-80% of patients
  • Start at a low dose to avoid temporary worsening of myasthenia gravis
  • Increase dose slowly until marked clinical improvement is seen
  • Maintain this dose for 1-3 months then, when remission occurs, reduce to minimum effective dose given on alternate days
  • Patients need to be observed closely for adverse effects

Immunosuppressants

  • Should be considered in patients with progressive myasthenia gravis symptoms

Azathioprine

  • Extensively used steroid-sparing immunosuppressant
  • Most widely used of the immunomodulatory agents
  • May be combined with corticosteroids to add therapeutic effect &/or allow the steroid dose to be reduced
  • May take 4-12 months to see beneficial effects, with maximum effect seen at 6-24 months

Ciclosporin

  • May be as effective as Azathioprine; may be used alone but is usually combined with steroids 
    to allow for a reduction of steroid dose
  • Considered a third-line therapy; should be used only in patients intolerant or unresponsive to other immunosuppressants (eg Azathioprine)
  • Beneficial effects are seen in 1-3 months

Cyclophosphamide

  • Demonstrated to be effective in treatment-resistant myasthenia gravis cases
  • Risk of adverse events limits its use
Eculizumab
  • Approved by the United States Food & Drug Administration (US FDA) & European Medicines Agency (EMA) for refractory generalized myasthenia gravis that is AChR antibody-positive
  • A humanized monoclonal antibody that binds to C5 & inhibits the formation of C5b-induced membrane attack complex

Mycophenolate

  • Maybe considered for long-term therapy if refractory to 1st-line treatment
  • Has been shown in small studies to improve functional status or as a steroid-sparing agent
  • May be better tolerated than other immunomodulators due to its relative lack of side effects
  • Drug is costly & beneficial effects may take months to be seen

Intravenous Immunoglobulin (IVIg)

  • May be used to treat myasthenia gravis crisis or to improve a patient’s condition prior to thymectomy or as an adjuvant to minimize side effects with long-term immunosuppressant therapy
  • Rapid improvement occurs in 70% of patients within 4-5 days of treatment
    • Can be used in the presence of systemic infection
    • Beneficial effect may last for weeks-months
  • Drug is expensive
Other Therapies
Rituximab
  • In studies, it appears to be particularly effective in patients with MuSK-positive myasthenia gravis that often respond relatively poorly to first-line immunosuppressive therapies

Non-Pharmacological Therapy

Plasmapheresis

  • May be used to treat myasthenia gravis crisis or to improve a patient’s condition prior to thymectomy
  • Pathogenic antibodies are separated from the blood cells mechanically
  • Useful in decreasing symptoms when starting immunosuppressive therapy
  • 5 exchanges (3-4 L/exchange) are performed over a 2-week period
  • Rapid short-term clinical improvement in most patients due to reduction in anti-AChR antibodies
  • Not recommended in patients with cardiac failure, sepsis, hypotension & pregnancy
  • Not recommended as a treatment to obtain a continuous & lasting immunosuppression in myasthenia gravis
  • Not considered to be a suitable procedure in pediatric patients
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