Prevalence and Pathophysiology of Myasthenia Gravis


A. Gordon Smith, MD, FAAN, reviews prevalence and subtypes of myasthenia gravis. He also discusses how different antibodies contribute to the pathophysiology of the disease.

A. Gordon Smith, MD, FAAN:Myasthenia gravis is a disease of neuromuscular junction transmission that causes muscle weakness and fatigue. In this context, the fatigue is really progressive weakness or worsening weakness with activity, although patients also have general fatigue. The disease often starts with ocular symptoms, so drooping eyelid, ptosis, or diplopia or double vision. In most patients, probably about 60%, it progresses to generalized myasthenia. This may involve bulbar muscles with dysarthria and dysphagia or weakness of limb muscles, trunk muscles, or breathing muscles. That progression usually takes place within the first one to two years, if not earlier. Myasthenia gravis is an uncommon disease. It affects about 1 in every 100,000 people in the United States. It impacts kids as well as the elderly, so it's an equal offending customer, as it were. Generally speaking, younger women and older men develop myasthenia gravis.

The underlying pathophysiology of myasthenia gravis is deceptively complicated. We really think of this as a B-cell mediated antibody-mediated disorder, which it is, but it's also T-cell dependent. It's important for us to remember this is the case, particularly with new therapies coming down the pipeline. But the tip of the sword is really in B-cells and antibodies. Most patients who have myasthenia gravis have a detectable antibody that essentially attacks the postsynaptic neuromuscular junction. The most common antibody are antibodies that bind to the acetylcholine receptor. 85% to 90% of people, depending on how you measure with myasthenia gravis, have ACHR antibodies. These cause the problem in multiple different ways. The first is these antibodies can block the acetylcholine receptor, which prevents the acetylcholine from interacting with it and therefore causes muscle weakness and fatigue. But they also modulate. Modulating antibodies crosslink the acetylcholine receptors, and this causes the receptors to be endocytosed into the postsynaptic membrane and degrade it. Of course, if you lose the receptor, that causes difficulty in neuromuscular junction transmission. Then lastly, there are binding antibodies. Binding antibodies do just that. They bind to the acetylcholine receptor, but in doing so, they then kick off or fix complement or the complement cascade that ultimately leads to structural damage to the neuromuscular junction. These different mechanisms are important to understand in thinking through the different treatments that we have for myasthenia gravis. When I was in training, we thought blocking was the thing, and that definitely is a thing, but now we know that complement-mediated destruction of the neuromuscular junction is important, as well.

The other antibody we think about frequently in myasthenia gravis is that which binds to muscle-associated tyrosine kinase or MuSK. Anti-MuSK antibodies are seen in about 5% of patients. They are pretty uncommon. While the phenotype of this disorder is distinctly myasthenic, it is a bit different than typical ACHR-mediated myasthenia gravis in that it tends to be a more difficult disease to manage. It's more often bulbar, more often respiratory, or axial. It disproportionately affects younger women. It's also mediated by an IgG4 antibody. This is relevant because IgG4 does not fix complements. You wouldn't use complement inhibitors in this disease. Then there are 10% to 15% of patients who are seronegative. Some of these patients will have one of a variety of other very uncommon antibodies that are not as clinically meaningful as MuSK or ACHR, but management of seronegative myasthenia presents its own challenges.

Most patients with myasthenia gravis have as their first symptoms, as I already mentioned a moment ago, said double vision or drooping eyelids. It's not uncommon for patients with myasthenia to initially present to an optometrist or an ophthalmologist. When that happens, the path to get to a neurologist who usually is the type of physician who diagnoses myasthenia gravis is relatively quick. A patient who presents with muscle fatigue and muscle weakness can take a little longer. They often present to their primary care doctor, but there, too, the referral is often made to a neurologist. The diagnosis is usually made by a general neurologist or a comprehensive neurologist or a neuromuscular neurologist. Fortunately, the path to diagnosis for most patients is perhaps less tortuous or delayed than can be the case with others, similarly uncommon or rare diseases, but sometimes it does take a while.

Transcript edited for clarity

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