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Myasthenia gravis

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Myasthenia gravis

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Myasthenia gravis

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Preview

A 72-year-old man comes to the office because of intermittent fatigue and weakness, especially in the evenings. He says that his head sometimes feels too heavy for his neck, and it is even difficult for him to smile. Physical examination shows a drooping left eyelid that improves with administration of edrophonium. Which of the following is the most likely underlying mechanism of this patient's condition?

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Transcript

Content Reviewers:

Rishi Desai, MD, MPH

Contributors:

Tanner Marshall, MS

Myasthenia gravis, is a Latin expression that literally means “grave muscle weakness,” which perfectly describes the weakness that happens when this autoimmune disease affects the skeletal muscles.

People with myasthenia gravis might wake up feeling fine, but get progressively weaker as the day goes on and by the end of the day they might feel very weak, sometimes even getting weaker with repetitive movements like chopping vegetables.

Myasthenia gravis can affect the extraocular muscles, which control movement of the eye as well as the eyelids, so individuals might have diplopia or double vision, as well as ptosis, or drooping eyelids.

Myasthenia gravis preferentially affects young women in their 20s and 30s and older men in their 60s and 70s, but the cause of this odd “bimodal” distribution of age-of-onset isn’t quite clear.

To better understand myasthenia gravis, let’s review normal muscle contraction but at the cellular level.

First you’ve got your motor neurons that release the neurotransmitter acetylcholine at the neuromuscular junction, which then binds to nicotinic acetylcholine receptors on muscle cell membranes.

Binding of acetylcholine to its receptor activates a chain reaction in the muscle cell that ultimately results in muscle contraction.

But what happens in myasthenia gravis though? Well remember that it’s an autoimmune disease, specifically one that’s categorized as a type II hypersensitivity which causes cytotoxic injury meaning that it results in the lysis or death of host cells, which is mediated by autoantibodies, which are antibodies that are specific for our own cells or proteins.

Alright, so in this case, the patient’s B cells inappropriately make antibodies that bind to nicotinic acetylcholine receptors on the muscle cells.

Once acetylcholine receptors are bound by the antibody, they are unable to bind to acetylcholine, and therefore don’t respond to the “contract” signal from the central nervous system.

Anti-acetylcholine receptor antibodies can also activate the classical pathway of the complement.

The complement system is a family of small proteins that work in an enzymatic cascade to fight off bacterial infections.

The activation of complement causes inflammation and destruction of the muscle cells and reduces the amount of acetylcholine receptors on the surface.

Now a minority of people with myasthenia gravis produce another type of harmful antibody called muscle specific receptor tyrosine kinase antibodies, which attack proteins inside of muscle cells instead of nicotinic acetylcholine receptors on the muscle cell surface, but they similarly lead to destruction of healthy cells.

Summary
Myasthenia gravis is an autoimmune neuromuscular disease that leads to fluctuating muscle weakness and fatigue. In the most common cases, muscle weakness is caused by circulating antibodies that block acetylcholine receptors at the postsynaptic neuromuscular junction, inhibiting the excitatory effects of the neurotransmitter acetylcholine on nicotinic receptors at neuromuscular junctions. Alternatively, in a much rarer form, muscle weakness is caused by a genetic defect in some portion of the neuromuscular junction that is inherited at birth as opposed to developing through passive transmission from the mother's immune system at birth or through autoimmunity later in life.
Sources
  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Harrison's Principles of Internal Medicine" McGraw Hill Education/ Medical (2018)
  3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill Education / Medical (2018)
  4. "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education / Medical (2019)
  5. "Ephedrine for myasthenia gravis, neonatal myasthenia and the congenital myasthenic syndromes" Cochrane Database of Systematic Reviews (2014)
  6. "The myasthenic patient in crisis: an update of the management in Neurointensive Care Unit" Arquivos de Neuro-Psiquiatria (2013)