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
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.