Acetylcholine and Myasthenia Gravis

How does the neuromuscular junction work?

The neuromuscular junction is the connection between a motor nerve and muscle fiber.

The activated motor nerve triggers the release of acetylcholine (ACh), which then diffuses across the neuromuscular junction to the muscle (post-synaptic) membrane, binds to any available acetylcholine receptor (AChR), which then in turn  activates the muscle fiber, ultimately leading to a motor contractions and a volitional movement.

What happens in myasthenia?

Autoimmune (acquired) myasthenia gravis (MG) is caused by antibodies circulating in the blood stream which bind to AChRs and disrupt neuromuscular transmission in a variety of ways:

Some of these antibodies simply block the receptor’s binding sites so that ACh cannot activate the muscle membrane:

mg1

Other antibodies link the receptors together:

mg2

Which then leads to internalization of the receptors (endocytosis) and simplification of the post-synaptic membrane:

mg3

The end result is that the post synaptic membrane becomes simplified and devoid of working AChr, so there are little or no available binding sites for the released ACh to bind to:

mg4

Excess ACh is removed from the synaptic cleft by the enzyme acetylcholinesterase (AChE), which breaks it down into inactive constituents.

nmj achr

So, you can think of MG like a game of musical chairs, when some of the chairs have been taken away, and there some of the acetylcholine can’t find a place to sit down before it is gobbled up by the AChE.

musical chairs

You can tip the odds more in favor of facilitating neuromusucular transmission by inhibiting AChE, allowing ACh to stick around longer, making it more likely to find an available AChR to bond to, rather like waiting longer to remove the chairs in musical chairs.

Dr Mary Walker first uses physostigmine in MG

mg mwDr Walker was first to discover the benefits of using a acetylcholinesterase inhibitor (AChEI) in MG in 1934.  While still a house physician at St Alfege’s Hospital, Greenwich, she found herself taking care of a 56-year-old woman with severe MG.  She happened to review the case with visiting neurologist, Dr Denny Brown, who explained to Dr Walker that MG resembled the effect of curare poisoning. Dr Walker, reading that the effect of curare could be reversed by injecting physostigmine, tried this drug on her patient, with remarkable improvement. She then treated a second case, a 40-year-old woman, using prostigmine, marketed by Roche. This case was presented to the Royal Society of Medicine in December 1934, and became known as ‘The Miracle of St Alfege’s’.

The Tensilon Test

We do still (rarely) use injectable AChEIs  like prostigmine (neostigmine) for managing MG.

However, we now more often use them for diagnosing MG, and in particular the short acting drug edrophonium or Tensilon has become synonymous with the diagnosis of MG, the so-called Tensilon test.

Mestinon

The oral AChEI pyridostigmine or Mestinon is now widely prescribed for symptomatic treatment of MG

Drooping eyelids (ptosis)

Ptosis can affect one or both eyes and results from weakness affecting the muscles that raise the eyelid.

L ptosis

Left sided ptosis

Ptosis can be congenital (you are born with it), or acquired (it develops during life).

Acquired ptosis can result from a variety of problems affecting the nerves, muscles, neuromuscular junction or tendons involved in elevating the eye lids.

Neurogenic ptosis is usually unilateral, and can be caused by a lesion affecting either the oculomotor nerve or the sympathetic nerve fibers to the eye (Horner’s syndrome).

When ptosis is caused by an oculomotor nerve lesion, there is  generally also some degree of eye movement abnormality (ophthalmoparesis).  Oculomotor nerve palsy can be caused by something as simple as diabetes, but if the nerve fibers to the pupil are involved (causing a dilated pupil in addition to the ptosis and ophthalmoparesis), that is very suggestive of a compressive lesion such as an aneurysm (see below) and warrants immediate evaluation.

R ptosis, occulomotor palsy (eye is deviated down and outwards), with a dilated pupil, caused by nerve compression from aneurysm (red arrow)

R ptosis, oculomotor palsy (eye is deviated down and outwards), with a dilated unreactive pupil, caused by nerve compression from aneurysm (red arrow)

Horner’s syndrome causes mild ptosis associated with a small pupil (miosis) sometimes associated with lack of sweating (anhidrosis) on the face, and can be caused by trauma to the carotid artery, lung tumors, or strokes.

L Horner's syndrome with mild ptosis and miosis

L Horner’s syndrome with mild ptosis and miosis

Myasthenia gravis is an autoimmune disease that affects the neuromuscular junction, and frequently presents with fatiguable ptosis often associated with double vision and limb weakness.   The ptosis will usually get worse when the patients is tired at the end of the day (diurnal variation):

Fatiguable ptosis in myasthenia gravis

Fatiguable ptosis in myasthenia gravis

The ptosis of myasthenia can be temporarily improved with an acetylcholinesterase inhibitor medication, such as an injection of edrophonium (Tensilon), and this can used a diagnostic test.

Ptosis can also be seen in certain muscle diseases, including oculopharyngeal muscular dystrophy, mitochondrial myopathy and myotonic dystrophy.

Bilateral ptosis in a patient with myotonic muscular dystrophy

Bilateral ptosis in a patient with myotonic muscular dystrophy

However, acquired ptosis is most commonly caused by dehiscence or disinsertion of the levator aponeurosis, causing a disconnection between the eye lid and the elevating muscles.

This usually occurs in elderly patients, but can sometimes affect younger contact lens users.

L ptosis from levator dehiscence - Note that when the eye is closed, the lid crease is fainter and further away from the lid margin in the left eye, compared to the right eye

L ptosis from levator dehiscence – Note that when the eye is closed, the lid crease is fainter and further away from the lid margin in the left eye, compared to the right eye

Patients who notice a drooping eyelid, unequal pupils, or double vision should consult with a neurologist in order to establish the correct diagnosis.

After that, treatment might include medical therapy for an underlying disorder (such as diabetes or myasthenia), surgery or even eye lid crutches:

Myasthenic patient with isolated L ptosis, demonstrating improvement with the eye lid "crutch"

Myasthenic patient with isolated L ptosis, demonstrating improvement with the eye lid “crutch”