Written by Gareth Brown and Louise Milburn
4th year medical students
(with occasional editorial input, mostly the opinionated parts, from me!)
Myasthenia Gravis (MG) is a rare, long-term condition that causes certain muscles to become weak.
(Ed - Being rare is no excuse for not being able to diagnose it, however.)
It tends to affect muscles which are responsible for voluntary movement, particularly those involving the eyes and eyelids, facial expression, chewing, swallowing and speaking.
Occasionally, muscles involved in respiration, and movement of the neck and limbs are affected.
Untreated, it is life-threatening; patients can present in crisis, requiring intensive care support and prolonged admission.
Diagnosis is often delayed, as MG rarely enters into the differential diagnosis at the outset.
What causes MG?
Myasthenia Gravis is an autoimmune disorder of the neuromuscular junction.
When the electrical signal, from a nerve, reaches the neuromuscular junction, it is unable to cross the synapse, so a chemical called a neurotransmitter is required to bridge the gap; in this case, acetylcholine.
The electrical signal causes the release of acetylcholine from stores, known as vesicles. Acetylcholine crosses the gap, or synapse, and interacts with a nicotinic receptor on the opposite side.
When acetylcholine binds to its receptor, an intracellular cascade occurs, which generates a new electrical signal, stimulating the muscle.
Fig. 1: A normal neuromuscular junction.
In most cases of MG, acetylcholine receptors are either blocked, or destroyed, by autoimmune antibodies. This blocking of the neuromuscular junction prevents signals from reaching the muscles, resulting in muscle weakness and problems with voluntary movement.
Less commonly, antibodies target the MuSK (muscle-specific kinase) protein. MuSK is one of the proteins involved in the intracellular cascade. This produces the same symptoms/signs as regular MG, and treatment is the same.
Fig. 2: A neuromuscular junction in Myasthenia Gravis
How does MG present?
Most commonly, patients with MG present with symptoms affecting eye movement.
50% of people presenting with the disease, initially present with either double vision or drooping of the eyelid.
90% of sufferers experience these at some point in their lives.
Other symptoms include:
- Nasal regurgitation of liquids
- Jaw ache on chewing
- Head drop (due to neck extension weakness)
- Limb weakness
- Respiratory compromise
The more of these symptoms your patient has, the greater the emergency. Never leave a myasthenic patient at home if they report respiratory symptoms or problems swallowing.
This is a neurological emergency.
Weakness in MG is described as fatiguable. This means that sometimes a movement can be initiated, but the person is unable to maintain it. Symptoms are at there best early in the day, and worsen as the day progresses.
Sensation is not affected, as only the motor nerves contain a neuromuscular junction.
Reflexes will be normal, as the afferent pathway is not affected, and there are enough residual acetylcholine receptors to effect a response.
I’m very grateful to Doreen for allowing me to show this video online. The start of the footage shows her presentation, with facial weakness, dysarthria, dysphagia and some muscle weakness. She has responded really well to medical treatment, as you can see, and is back dancing again.
Clinical history and neurological examination confirmed by:
- Nerve conduction studies can demonstrate fatigability with repeated stimulation. A decrease of amplitude of action potential of over 10% is considered abnormal. Electromyography (EMG) can demonstrate disruption in signals from the nerve to the muscle – this is known as neuromuscular block and jitter.
- Serum antibody tests – looking for antibodies to skeletal muscle nicotinic acetylcholine receptor (AChR), which are positive in 85% of patients with generalised MG, and 50% of pure ocular MG. 8-10% of patients with generalised MG will have MuSK antibodies (muscle-specific tyrosine kinase receptor) which is an enzyme involved in the AChR clustering in the synaptic cleft.
- Edrophonium (Tensilon) test. Edrophonium chloride prevents acetylcholine from being broken down, which temporarily increases the amount of acetylcholine around the muscle, giving a brief increase in muscle power.
- Ice testing involves placing an ice pack over the eyelid and then looking for an improvement in ptosis and diplopia. The rationale for this is that cooling might improve neuromuscular transmission. It has now been demonstrated however (Movaghar M, 2000) that ice, heat ,and rest all have the effect of improving ocular MG temporarily, so it is thought to be a rest effect.
No test is more than 80% specific so, at times, you may be left with a patient who clinically has myasthenia, but has negative test results for all of the above. In these cases you could use pyridostigmine – one of the treatments for the symptoms of myasthenia and judge the clinical response.
In MG patients, it is also important to do a CT chest to look for enlargement of the thymus gland. This could be a tumour (a thymoma) or thymic hyperplasia.
Check out this Tensilon (edrophonium) test in a doggie. I kid you not, it is this dramatic in humans too! We tend not to do too much of this now, as accessibility to NCS/EMG is much better. That said, at a weekend, where I really want to nail the diagnosis, and there is no hope of getting an EMG and NCS, then this can be a really useful thing to do.
Dependent on severity the of symptoms, treatments may be used to control symptoms and to induce remission.
If a MG patient presents in crisis, a more aggressive approach may be used. These patients often need to be assessed following an ABCDE approach, and can require ITU. Plasma exchange may be used in these patients to remove the circulating antibodies. IVIG can also be used to dampen down the immune response; 65% of patients with MG respond to IVIG therapy (Zinman L, 2007).
For patients not in crisis, pyridostigmine can be used to control symptoms. Pyridostigmine is an acetylcholinesterase inhibitor, which prevents the breakdown of acetylcholine in the neuromuscular junction. Its side-effects include stomach cramps, diarrhoea, nausea and muscle twitching.
Regular prednisolone may be used to induce remission by damping down the immune system. These are often prescribed on a reducing dose, to try to limit side-effects (weight gain, easy bruising, diabetes and osteoporosis).
Other immunosuppressant’s like azathioprine, mycophenolate and methotrexate may also be used to induce remission, and as steroid-sparing agents.
Thymectomy should also be considered for suitable patients. Thymoma or thymic hyperplasia can be removed surgically, and, in some patients, this can reduce symptoms and make their MG more easily controlled in time (Takanami I, 2009).
Surgery is not recommended for some patients, i.e. those with MusK antibody-positive MG and patients at the extremes of age (Leite MI, 2005).
You can do worse than this eMedicine article on myasthenia.
The are also a couple of excellent review articles from practical neurology.
Jacob et al. Myasthenia gravis and other neuromuscular junction disorders. Pract Neurol. 2009 Dec;9(6):364-71.
Sussman et al. Myasthenia gravis: Association of British Neurologists’ management guidelines. Pract Neurol. 2015 Jun;15(3):199-206.
Leite MI, S. P. (2005). Fewer thymic changes in MusK Antibody-positive than in MusK antibody-negative MG. Ann. Neurology (1132), 264-70.
Movaghar M, S. M. (2000). Effect of local heat versus ice on blepharoptosis resulting from ocular myasthenia. Opthalmology , 107 (12), 2209-14.
Takanami I, A. T. (2009). Therapeutic outcomes in thymectomied patients with myesthenia gravis. Ann. Thorac Cardiovasc Surg , 57 (3), 444-8.
Zinman L, N. E. (2007). IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology , 68 (11), 837-41.