Myasthenia gravis is a syndrome of
weakness and fatigue due to dysfunction of the neuromuscular
junction. It is an antibody-mediated autoimmune condition with a
range of moderately effective treatments. Occasionally patients
go into remission spontaneously, but most require treatment.
Mild disease, such as that confined to the ocular muscles, can
often be treated with pyridostigmine alone. More significant or
generalised weakness requires immunosuppression, principally
with prednisone and azathioprine. The response to
immunosuppression is slow, ranging from several months to 1-2
years for a full response. Short-term use of antibody-based
therapy such as plasma exchange or intravenous immunoglobulin is
warranted for more severely affected patients. Thymectomy offers
the hope of drug-free remission but as yet remains unproven.
Treatment-related morbidity is considerable, but partly
Key words: azathioprine, immunosuppression, prednisone,
(Aust Prescr 2007;30:156-60)
Myasthenia gravis is an autoimmune disease which causes muscular weakness due to dysfunction of the neuromuscular junction (Fig. 1). Autoantibodies directed against antigenic proteins on the postsynaptic side of the neuromuscular junction result in both blockade of transmission and damage to the postsynaptic structure. As a result the motor neuron is unable to 'talk' to the muscle fibre and weakness results. The known antigens to which the autoantibodies bind are the acetylcholine receptor and, less commonly, muscle-specific tyrosine kinase.
The prevalence of myasthenia gravis is about 1 in 10 000. The gender ratio is approximately equal, with a peak incidence of onset in the 20s for women and the 60s for men. Around 10% of patients with a positive acetylcholine receptor antibody test have an associated thymoma.
|Normal muscular junction |
|In the normal neuromuscular junction, acetylcholine released from the nerve terminal following a nerve action potential, binds to the acetylcholine receptor on the postsynaptic muscle, triggering a muscle action potential propagated by the voltage gated sodium channel. Acetylcholinesterase scavenges and breaks down unbound acetylcholine. In a separate pathway, neural agrin binds muscle specific tyrosine kinase initiating clustering of phosphorylated rapsyn and acetylcholine receptors, stabilising the postsynaptic structure opposite the nerve.|
In myasthenia gravis caused by antibodies to the acetylcholine receptor, there is blockade of the binding site for acetylcholine, cross-linking of the acetylcholine receptor with subsequent internalisation and reduction in its surface expression, and initiation of complement and cellular inflammatory cascades with damage to the post- and presynaptic structures. The molecular physiology of myasthenia gravis mediated by antibodies to muscle specific tyrosine kinase has not been established.
There are a range of diagnostic tests for myasthenia gravis. These include dynamic tests for measuring muscle weakness (for example, response to edrophonium or ice pack), electrical tests such as repetitive stimulation or single fibre electromyography, and measurement of antibodies to acetylcholine receptor and to muscle-specific tyrosine kinase.
Myasthenia gravis affects some regional muscles more than others. Most commonly the orbital muscles are affected first, with either diplopia or ptosis. However, myasthenia gravis may first affect the bulbar muscles (speech and swallowing), the neck muscles (head drops) and proximal or rarely distal limb or respiratory muscles. Involvement is fairly symmetrical except in the eyes. Symptoms may get worse towards the end of the day or after a few minutes of continuous use - for instance speech may become slurred over a few minutes. More severe myasthenia gravis affects multiple muscular regions and may be sufficiently severe to cause respiratory failure and death if untreated.