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
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.
|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.
Natural history of myasthenia gravis
Generally, myasthenia gravis is a persistent disease
requiring chronic treatment. Fluctuations over the long term are
the norm. Some patients go into long-term remission
spontaneously - approximately 15-25% after five years for those
presenting with generalised disease and somewhat more for those
presenting with ocular disease only. Late relapse after
sustained remission also occurs, the longest reported example
being after 32 years. It should be noted that the neuromuscular
junction can be reformed, unlike many parts of the nervous
system. Muscle strength that has been affected by myasthenia
gravis for a long time often recovers with treatment. This means
that the intensity of treatment for myasthenia gravis can be
modulated to the current severity of the disease.
Over time, patients with clinically isolated ocular
myasthenia gravis often progress to generalised myasthenia
gravis. Treatment with corticosteroids can reduce the likelihood
of progression, and control both ocular and generalised weakness
completely in many cases. It is not known if this alters the
natural history or the need for long-term treatment. It is
therefore unclear whether treatment should be commenced for
ocular disease or just 'as required' to control symptoms that
are causing sufficient disability to justify the adverse effects
of treatment. Long-standing ocular misalignment may not recover
despite generalised remission.
The diagnosis must be confirmed before treatment, because the
mainstay of treatment for most patients is immunosuppression.
Treatments to prevent the adverse effects of immunosuppression
should be started simultaneously with the therapy (see
Table 1). There is no robust evidence that long-term
treatment actually cures the condition, so some patients choose
to avoid the adverse effects of immunosuppressive therapy and
accept degrees of weakness. Coping without treatment is not
always the safest strategy as patients with significant
weakness, particularly in the bulbar musculature, are at risk of
ventilatory failure or of needing intensive care following an
intercurrent respiratory infection. Immunosuppressive treatment
is therefore strongly recommended for control of significant
Initial treatment is usually with pyridostigmine, followed by
prednisone and azathioprine if the response is incomplete. A
combination of approaches is often useful to cover deficiencies
in each available drug.
Immunosuppression produces a very slow response, often taking
many months to 1-2 years.1,2
An unrealistic expectation of a speedy response is
often a problem for both the patient and the doctor.
There are four main approaches to treatment, each with very
different durations of effect, requirements, consequences and
Prophylaxis of the
complications of immunosuppression
density before treatment and yearly while on
treatment. Start calcium and vitamin D
supplements. Bisphosphonates may reduce bone
loss associated with the chronic use of
||Risk factor modification should
be standard and includes advice to stop smoking,
start an exercise program and manage
screening and prophylactic treatment with proton
pump inhibitors or H2 antagonists
seems appropriate for those with a past history
of previous ulceration or concordant use of
non-steroidal anti-inflammatory drugs.
||Use of inactivated vaccines
such as influenza is recommended. Live vaccines
are contraindicated. A chest X-ray should be
performed prior to treatment. More specific
testing for tuberculosis may be indicated
depending on history and chest X-ray results.
rates are increased in patients using
azathioprine. A full yearly dermatological
survey is recommended. Exhort sun protection and
cancer surveillance. Regular cervical smears are
recommended. Eye protection may also limit
Improve neuromuscular transmission
by inhibiting acetylcholinesterase
Drugs that inhibit acetylcholinesterase include
pyridostigmine, edrophonium (used only for testing) and
neostigmine (for intravenous use in intensive care units only).
These drugs take effect within minutes and last for hours.
Although they are without long-term adverse effects, the
efficacy of all acetylcholinesterase inhibitors is limited. As a
sole drug they are not enough for most patients with generalised
Pyridostigmine is the first-line treatment for myasthenia
gravis. It is a reversible inhibitor of acetylcholinesterase so
increases acetylcholine stimulation of the remaining
acetylcholine receptors. If there are insufficient acetylcholine
receptors remaining to trigger a muscle action potential, extra
acetylcholine from the action of the drug is not going to help.
The underlying autoimmune state is not altered. It is often
sufficient for ptosis alone, but not for diplopia or generalised
myasthenia gravis. Benefit is often not sustained, possibly due
to counterproductive upregulation of acetylcholinesterase and
downregulation of acetylcholine receptors. The dose required is
variable, as is gastrointestinal tolerance. One approach is to
start at 10 mg three times a day and titrate up to 60 mg 4-6
times daily. A 180 mg 'timespan' preparation is available for
nocturnal symptoms. In practice a degree of patient control of
dosing and 'when required' use is often helpful.
Doses less than 480 mg daily rarely produce depolarising
crisis. Increasing weakness after an increase in the
pyridostigmine dose (when high doses are already being given)
suggests deteriorating disease and/or a depolarising crisis.
This may require treatments such as plasma exchange and a
reduction in pyridostigmine dose. The presence of
gastrointestinal adverse effects and fasciculations, clinically
or on electromyogram, might suggest depolarising crisis. The
patient must be hospitalised and the dose of pyridostigmine
reduced while they are carefully monitored. Lack of improvement
with edrophonium (which has a very short half-life) indicates
that further pyridostigmine will not be useful.
The principal drugs used to suppress the immune system in
myasthenia gravis are prednisone (a glucocorticoid) and
azathioprine. The response to these treatments can take weeks to
many months, with the maximal effect taking months to years.1,2
Prednisone or another corticosteroid is the primary
immunosuppressant used in myasthenia gravis. Sustained
improvement or remission can be achieved while patients remain
on treatment. A typical course for generalised myasthenia gravis
would use 1 mg/kg prednisone daily (0.5 mg/kg for ocular
myasthenia gravis) until clinical control is achieved and then
weaning either directly or by initial conversion to alternate
daily dosage, with the determination of a maintenance dose by
trial and error during a slow withdrawal of medication over many
months. Deterioration in myasthenia gravis can occur in the
first few weeks of treatment so the dose is often increased
slowly. The mean time to maximal effect of prednisone in
myasthenia gravis is six months - much longer than most expect.
Azathioprine is used as a steroid sparing drug and additional
immunosuppressant with prednisone. In a randomised trial, after
three years of treatment, 63% of patients with myasthenia gravis
taking azathioprine were off all prednisone, versus 20% taking
placebo, but no effect was seen in the first year.2
Compared to the metabolic consequences of continued
corticosteroids, the problems of azathioprine seem significantly
less. However, the long-term consequences do include an
increased risk of skin cancers and a small possible increase in
the risk of haematological malignancies. About one-fifth of
patients cannot take azathioprine due to rash, hepatitis,
myelosuppression, nausea or vomiting, but this is usually
evident within two weeks to two months. Some doctors routinely
use azathioprine for patients with generalised myasthenia gravis
still requiring more than 10 mg prednisone per day at six
months, or if severe disease is obvious earlier.
If not using azathioprine, other steroid-sparing drugs used
include mycophenolate mofetil, cyclosporin, methotrexate and
cyclophosphamide. Experience with these drugs is generally
derived from retrospective series. None of these have proven
efficacy in randomised trials except for cyclophosphamide, and
choice of drug depends on age and competency of the patient plus
local experience of the physician. In practice they are
frequently used with apparent success, but like azathioprine the
response is often slow.
Mycophenolate mofetil is a pharmacologically similar
alternative to azathioprine but two recent randomised controlled
trials failed to demonstrate benefit in myasthenia gravis.*
The duration of both trials was less than a year. As it works in
the same pathway as azathioprine this may have been inadequate
and it remains widely used.
Rituximab, a monoclonal antibody specific to CD20 (on B
cells), or bone marrow ablation with autologous transplant are
treatments of last resort.
Remove or block autoantibodies
Plasma exchange removes autoantibodies and intravenous
immunoglobulin is thought to block autoantibodies. These
treatments take effect within days, but only last weeks before
treatment needs to be repeated. They have a key role in
stabilising severe myasthenia gravis and in preparation for
surgery, or in pregnancy.
Plasma exchange is expensive and only available in major
hospitals. It requires good intravenous or alternatively central
catheter access, but a central line increases the risk of
infection. Intravenous immunoglobulin, a purified blood product,
is also very expensive and is in limited supply. Its mode of
action remains unclear.
Thymectomy has a possible immunomodulatory role in the
absence of thymoma. Results of a global randomised trial are
awaited.† The effect of a
thymectomy appears to take years. Non-randomised retrospective
data suggest there is an increased complete remission rate from
thymectomy when it is performed within 2-3 years of the onset of
disease. This treatment involves major surgery with midline
sternotomy, although minimally invasive approaches are becoming
available. Other than surgical complications there are no known
long-term adverse effects.
Thymectomy for thymoma does not on average improve myasthenia
gravis, but is required to remove the tumour.
Drugs that worsen myasthenia gravis
Neuromuscular blocking drugs used for intubation and muscle
relaxation in surgery cause profound deterioration in myasthenia
gravis with marked prolongation and severity of neuromuscular
dysfunction. The diagnosis of myasthenia gravis should be
considered if patients fail to breathe spontaneously or are weak
after an anaesthetic.
Aminoglycosides such as gentamicin partially block the
neuromuscular junction and dramatically worsen myasthenia
gravis. Beta blockers have a generally mild adverse effect
(adrenergic stimulus is mildly beneficial for myasthenia gravis)
and the need to use them should be carefully considered.
Anticholinergics of all types logically have a deleterious
effect on the neuromuscular junction. In practice a muscarinic
anticholinergic such as propantheline is sometimes used to
control the adverse effects of pyridostigmine on the gut. Many
other drugs have been cited as provoking deterioration in
myasthenia gravis or have myasthenia gravis listed as a
contraindication to use in the product information. This
includes tetracyclines and quinolones, which in practice are
only occasionally problematic. Sedatives such as narcotics and
benzodiazepines have no direct effect on the neuromuscular
junction but obviously are contraindicated if hypercapnia or
respiratory failure are a risk.
Myasthenia gravis is a readily treatable condition and many
patients can expect to have little disability. It should be
acknowledged that of the residual disability, a considerable
amount comes from the treatment. Attempts to re-establish immune
tolerance of the acetylcholine receptor to cure the condition
have not yet borne fruit. No revolution in treatment is expected
in the near future.
The author thanks Dr Marcella Cox for a critical review of
the manuscript and Mr Bob Haynes for graphic design of the
figure. The author gratefully acknowledges the support of the
Australian Myasthenic Association in NSW, the NSW Muscular
Dystrophy Association and the Muscular Dystrophy Association of
the United States of America.
1. Pascuzzi RM, Coslett HB, Johns TR.
Long-term corticosteroid treatment of myasthenia gravis: report
of 116 patients. Ann Neurol 1984;15:291-8.
2. Palace J, Newsom-Davis J, Lecky B;
Myasthenia Gravis Study Group. A randomized double-blind trial
of prednisolone alone or with azathioprine in myasthenia gravis.
Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis.
Drachman DB. Myasthenia gravis. N Engl J Med 1994;330:
Stephen Reddel is an investigator of the United States
National Institutes of Health (NIH) randomised clinical
thymectomy trial currently underway. The NIH has paid for a
trial workshop including travel. He has also received a
consultancy fee from Aspreva, marketing company of mycophenolate
mofetil for use in autoimmune diseases.
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