ACh – The Neurology Lounge

Myasthenia gravis (MG) is an iconic neurological disorder. It is classical in its presentation, weakness setting in with exertion and improving with rest. This fatigability is demonstrable in the laboratory when repetitive nerve stimulation (RNS) of the muscles results in a progressively decremental response. Clinically, myasthenia gravis is often a benign disorder which restricts itself to the muscles of the eyes: this ocular MG manifests just with droopy eyelids (ptosis) and double vision (diplopia). At the extreme however is generalised MG, a severe and life-threatening condition that justifies its grave appellation.

By Posey & Spiller – Posey & Spiller: Fatigue (Ptosis) in a patient with MG (ed. 1904), Public Domain, Link

Myasthenia gravis depletes the energy reserve of muscles, something which is entirely dependent on acetylcholine (ACh), a chemical released at nerve endings. After release, ACh traverses the neuromuscular junction (NMJ) to attach itself to the acetylcholine receptor (AChR), which is comfortably nestled on the surface of the muscle. This binding of chemical to receptor is a significant event, setting sparks flying, and muscles contracting. In myasthenia gravis, this fundamental process is rudely disrupted by the onslaught of acetylcholine receptor antibodies. These aggressive AChR antibodies, produced by the thymus gland in the chest, vent their rage by competitively binding to the receptor, leaving acetylcholine high and dry. Eventually, the rampaging antibodies destroy the receptor in an act of unjustified savagery.

Drosophilia Neuron. NICHD on Flickr. https://www.flickr.com/photos/nichd/29596368551/

In tackling myasthenia gravis, it is no wonder that neurologists first have to hunt down the ferocious AChR antibodies. They whisk off an aliquot of serum to a specialist laboratory, but waste no time in planning a counteroffensive, confident that the test will return as positive. The strategy is to boost the level of acetylcholine in the NMJ, tilting the balance in favour of ACh against the antibodies. The tactic is to zealously despatch a prescription for a drug that will block acetylcholine esterase inhibitor, the enzyme which breaks down acetylcholine. The neurologist then closely observes the often dramatic response, one of the most gratifying in clinical medicine; one minute as weak as a kitten, the next minute as strong as an ox. MG is therefore one disorder which debunks the wicked jibe that neurologists know so much…but do so little to make their patients better!

Drosophilia Neuromuscular Junction. NICHD on Flickr. https://www.flickr.com/photos/nichd/34754479075

Unfortunately for the neurologist, every now and then, the AChR antibody test result comes back as negative. In the past, the dumbfounded and befuddled, but nevertheless undaunted neurologist, will march on, battling a diagnosis of antibody-negative MG. Nowadays however, this not a comfortable diagnosis to make because AChR antibody is no longer the only game in town. We now know that there are many other antibodies that are jostling for commanding positions in the anti-myasthenia coalition. These include anti LRP4, cotarctin, titin, agrin, netrin 1, VGKC, and ryanodine. However, the clear frontrunner in this melee is anti-MUSK antibody, responsible for 30-50% of MG in which there are no AChR antibodies.

Anti MUSK syndrome has many distinguishing features that set it apart from the run-of-the-mill myasthenia gravis. Below are five distinctive markers of anti-MUSK syndrome:

Subjects with anti-MUSK syndrome are typically middle-aged women in their 3rd or 4th decades. This is younger than the usual age of people with AChR MG. Indeed neurologists now recognise typical myasthenia as a disease of older people.
People with anti-MUSK syndrome present with acute and prominent involvement of head and neck muscles. This results in marked swallowing and breathing difficulties. They are therefore at a higher risk of myasthenia crisis.
Single fiber electromyogram (sfEMG), a specific and reliable neurophysiological test of MG, is often normal in anti-MUSK syndrome. This is partly because the limb muscles are usually spared in anti MUSK syndrome.
People with anti-MUSK myasthenia often do not benefit from, nor do they tolerate, the acetylcholinesterase inhibitors which are used to treat MG. Indeed, these drugs may worsen anti-MUSK syndrome.
Thymectomy, removal of the thymus gland, is not beneficial in people with anti-MUSK syndrome, unlike its usefulness in AChR MG.