Myasthenia Gravis - The Mystery of Disappearing Weakness
You are at the office. It has been a long and tiring day. You are loaded on caffeine and trying to crunch in some extra working hours to be prepared for that big meeting coming up. But suddenly you notice that your vision becomes blurry and your eyes are shutting. No, you are not falling asleep. Your body has enough caffeine and adrenaline pumping to keep you up for the whole night. But your eyelids are not able to keep up with the rest of the body. Eyelids shut down. You panic.
Drooping of eyelids (Ptosis) could be because of various reasons, but one of the most common differentials in this scenario is myasthenia gravis.
Myasthenia Gravis is a disorder of neuromuscular transmission.
(Click here to know more about NMJ)
When an action potential reaches the nerve ending, it opens the voltage gated calcium channels and allows calcium influx into the nerve terminal. Calcium facilitates the release of acetylcholine from the nerve endings into the synaptic space. Ach binds to the receptors on the skeletal muscle and causes muscle contraction.
Myasthenia gravis is an autoimmune condition in which IgG autoantibodies are formed against the acetylcholine receptors (AchR). Like other autoimmune disorders, there is a breach in the immune tolerance in myasthenia gravis (click here to know more about immune tolerance). The thymus which is responsible for central immune tolerance is at the fault here. Presence of muscle like cells with AchR in the thymus triggers the production of autoantibodies. These antibodies destroy the AchR, disabling muscle contraction and leading to muscle weakness. Though the presence of anti – AchR antibodies is diagnostic of myasthenia gravis, about 15% of the patients might lack them. Such patients may have antibodies against proteins that are required for clustering of AchR at the neuromuscular junction – like the Muscle specific kinase (anti MuSK antibody) and low-density lipoprotein receptor related protein 4 (anti lrp4 antibody).
In some patients the weakness may be restricted to extra-ocular muscles – a condition called ocular myasthenia. In its most severe form, weakness of the diaphragm causes life threatening respiratory paralysis. This stage is called myasthenic crisis. At an acute stage like this, patients need to undergo plasmapheresis, a process by which the autoantibodies are removed from the blood. Intravenous Immunoglobulins (IVIg) also helps to stabilise the patient. In the long run, patients are put on anti acetylcholinesterase drugs like Pyridostigmine. By blocking the acetylcholinesterase enzyme, this drug increases the availability of Ach in the synapse which acts on the few remaining receptors and facilitate muscle contraction. However if the drug dose is not monitored, excess acetylecholine in the synapse would deploarise the muscle in rapid succession to an extent where muscle fatigue occurs. This state of drug induced muscle weakness is called cholinergic crisis and it mimics myasthenic crisis.
Since the thymus is at fault here, all patients with generalised myasthenia gravis, between puberty to 55 years of age are advised to undergo thymectomy, excised specimen usually shows thymic hyperplasia or a thymoma. Patients also benefit from steroid therapy and immunosuppresants like mycophenolate mofetil in the long run.
The closest differential diagnosis is Lambert Eaton myasthenic syndrome (LEMS). In LEMS the autoantibodies are directed against the voltage gated calcium channels. Calcium influx is blocked and as a result the release of acetylcholine is also blocked. Though these 2 entities present with similar clinical features, it is easy to differentiate them with a simple clinical test – the deep tendon reflex.
Deep tendon reflex (DTR) is a local reflex arc. In LEMS, since Ach is not released, DTR is absent initially. On repeated stimulation or on exercising the muscle, some calcium channels do open up and allow calcium to enter the nerve ending and Ach is released. DTR now becomes positive. In myasthenia gravis, Ach is always present in the synapse, hence the DTR is never affected. Another test to distinguish the two is Repetitive Nerve stimulation (RNS). A nerve is stimulated by small amplitude electric currents in cycle and the action potential generated is recorded. In LEMS, on stimulating a nerve with electric current initially shows no response. On repetitive stimulation, some Calcium channels open up and a response is recorded. On the contrary, in Myasthenia gravis nerve stimulation elicits a response for the first few attempts followed by a rapid decrease in the amplitude of action potential.
And thats how a drooping eyelid at the end of a long and tiring day could be a telltale sign of something grave!
Author: Soundarya V (Facebook)
Sources and citations
Daniel B. Drachman, and Anthony A. Amato. “Chapter 461 - Myasthenia Gravis and Other Diseases of Neuromuscular Junction.” Harrison's Principles of Internal Medicine, 19th ed., vol. 2, McGraw Hill , pp. 2701–2706.