Introduction

• Myasthenia Gravis is an acquired, autoimmune disease of the neuromuscular junction.
• Antibodies attack the Acetylcholine receptor.
• This results weakness in muscles, particularly the ocular, bulbar and proximal skeletal.
• “Fatigability” is a key symptom!
• The disease has a fluctuating pattern of ‘crises’ and remittances.
• Treatment is usually with Acetylcholinesterase inhibitors and immunosupression, however in crises other treatments may be needed.
• Despite this it is easily treated and patients have a good life expectancy.

Epidemiology

Aetiology

Pathophysiology

• B and T cell mediated IgG autoantibodies are created which attack the postsynaptic acetylcholine receptors at the neuromuscular junction.
• These antibodies block the acetylcholine receptor and prevent acetylcholine from binding to it. Therefore, the nerve signal is not fully transmitted, and the resultant muscle weakness is a result of incomplete stimulation, rather than an inherent disorder within the muscle.
• Acetylcholine only exists in the synapse briefly, before it is quickly broken down by acetylcholinesterase. Therefore, there is not a strong enough acetylcholine presence to overcome this blockade by the autoantibodies.
• The ‘fatigabiltiy’ seen in Myasthenia Gravis occurs because there is only a finite amount of acetylcholine in a nerve ending. With each subsequent release of acetylcholine with each new nerve impulse, less is released, and so there is even less chance of it overcoming the blockade caused by the antibodies, and hence the nerve signal becomes ‘weaker’ each time.
  • Acetylcholine concentrations do recover relatively quickly – within minutes.
• There is a very strong association with disorders of the THYMUS. In 75% of patients with Myasthenia Gravis there is hyperplasia of the thymus, and in 10% this becomes a thymoma.

Signs and Symptoms

1. Ocular- Ptosis and Diplobia
2. Bulbar-Dysphagia, Dysphonia, Dysarthria and weak/droopy face
3. Proximal muscles- Shoulders and Thighs
4. Axial – Neck and trunk, but also muscles involved in Respiration

The fatigability of muscles can be demonstrated by getting the patient to do a repetitive movement (e.g flap their arm’s) for 30-60 seconds. They also report that their symptoms get worse as the day wears on, and that their best times are in the morning, or after a sleep.

Limb reflexes are usually normal or brisk, and there are no sensory abnormalities.

Muscle wasting is usually not present, unless there is severe disease, or the patient has had the condition for a long time.

Investigations

• The traditional test for Myasthenia Gravis is the TENSILON test, in which patients are given two drugs, Edrophionium, which prevents breakdown of acetylcholine, and atropine to prevent cardiac side effects associated with Edrophionium. If the patient has myasthenia gravis, then within seconds there is a dramatic symptomatic improvement, however this goes after a couple of minutes.
• Blood tests for serum acetylcholine receptor antibodies are positive in over 85% of patients with Myasthenia gravis, and there may also be other autoantibodies present, usually against muscle, joints or the thyroid.
• Electromyography is used to measure how fatigable a muscle is. Electricity is used to repeatedly stimulate a muscle, fatigue can be seen. Single fibre electromyography is usually preferred, as stimulating a single motor unit (remember those, a motor neurone and the muscle fibres it supplies), a variability called a ‘jitter’ can be found.
• CT/ MRI scans are used to image the thymus, looking in particular for hyperplasia.
• Spirometry is important as it gives an indication as to how badly affected the respiratory muscles are. In some crises respiratory function is compromised, and urgent medical attention is needed.

Management

• As already mentioned the disease course is very fluctuating, with remitting periods and crises. There is no cure; however several cases of permanent remission have been reported post thymectomy or heavy immunosupression.
• Oral acetylcholinesterase inhibitors are used to prevent destruction of acetylcholine in the synaptic space. The doses of these are patient determined, as an overdose can cause a cholinergic crisis, but you don’t want to undertreat the condition. A commonly used one is Pyridostigmine, which has a very short half life, and lasts 3-5h.
• Immunosupression is often given in conjunction with acetylcholinesterase inhibitors. Corticosteroids (mainly Prednisolone) are the mainstay here and work in 70% of cases; however in some cases steroid-sparing agents such as Azathioprine may be needed. Immunosuppressive treatment should be started and increased in hospital because patients often deteriorate when starting the treatment and an improvement follows. Because of the increased falls risk, prevention of osteoporosis is vital, and so many patients are on several drugs to combat this.
• More recently immunomodulatory agents such as Methotrexate, cyclosporine and cyclophosphamide have found a place in the treatment of Myasthenia Gravis, however second or third line behind immunosupression.
• In crises, additional treatments such as the use of IV immunoglobulins or Plasmapheresis may be needed.
• The use of thymectomies is changing. Previously if a thymus was found to be hyperplasic, or a thymoma was present, then thymectomy was performed, however some consultants now prefer to take the thymus out as early as possible, as better prognoses have been noted, and as already mentioned permanent relapse has been obtained.

Prognosis

Flashcard

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy

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