Disorders of Neuromuscular

Transmission
Normal anatomy and physiology

In motor nerves, when the stimulus reaches the end of

the nerve terminal, acetylcholine is released from vesicles via
voltage-gated calcium channels. The acetylcholine crosses the
synaptic cleft and bind to acetylcholine receptors on the
postsynaptic muscle end-plate membrane. This result in
depolarization and subsequent contraction of the muscle. The
acetylcholine is then broken down by acetylcholinesterase,
which is bound to the basal lamina in the synaptic folds.
 Two main diseases of neuromuscular transmission
will be discussed in this class-----myasthenia gravis and
lambert-eaton myasthenic syndrome.
Myasthenia gravis

Myasthenia gravis is an acquired immunological

disorder, of unknown cause, in which antibodies are directed
against the postsynaptic acetylcholine receptor. This result in
weakness and fatiguability of skeletal muscle groups. The
most commonly affected muscles are proximal limb, and
ocular and bulbar muscles.
 There is an associated abnormality of the thymus in
patients with myasthenia gravis. Thymic hyperplasia is found in
70% of patients below the age of 40 years. In 10% of all patient
with myastrenia gravis, a thymic tumour is found, the incidence
increasing with age. In patient with thymoma, antibodies to
striated muscle may also be found.
There appears to be two distinct group of patients who
develop myasthenia gravis, split by age and sex:

Young women(20-35 years), who tend to have an acute,

severely fluctuating, more generalized condition, with
increased association with HLA-88 and HLA-DR3

Older men (60-75years), who tend to have a more oculobulbar

presentation.
 There is some crossover between the groups, and
myasthenia gravis is seen in young men and older women, but
much less frequently.
Clinical features

The most important clinical features is fatiguability,

carusing fluctuating weakness, which is worse after exercise and,
usually, at the end of the day.

Fatiguability can be demonstrated by exercising

affected muscles, making a patient in whom ptosis is sometimes
qpparent, look upwards for a few seconds. The ptosis will be
become apparent and the eyes may drift to the neutral position.
Similar manoeuvres can be carried out for the proximal limb
muscles.
 Limb reflexes are normal or hyperactive, but
fatigue on repeated testing. Muscle wasting occurs in 15%
of cases. Sensory examination is normal.
Investigations

Tensilon test: tensilon is a fast-acting anticholinesterase,

it antagonizes the action of acetylcholinesterase and thus
prevents the breakdown of acthlcholine, allowing this to
competitively compete with acetylcholine receptor antibodies.
When given as an intravenous bolus, usually with atropine to
prevent cardiac side effects, weakness is improved in seconds, the
effect lasting for 2-3minutes. It acts as diagnostic test for
myasthenia gravis.
Serum acetylcholine receptor antibody

The highly specific acetylchaline receptor antibody is

present in the serum of up to 80% of patients with
generalized myasthenia gravis.
Electromyagraphy

There are two classical electromyographic findings in

myasthenia gravis:

A decrement in amplitude of the compound muscle

action potential following repetitive stimulation,

Increased jitter using a single-fibre electrode.

Thymus imaging

It is always essential to image the chest with computed

tomography or magnetic resonance imaging, for the
presence of thymic hyperplasia or tumour, as removal of a
hyperplasia or tumour, as removal of a hyperplastic thymus
improves the condition in many patients.
Autoantibodies

Other autoantibodies may be present, especially

those against striated muscle and thyroid.
Management

The illness may have a protracted and fluctuating

course. Acute exacerbations may be unpredictable or may
follow infections or treatment with certain drugs. It is
important to recognize respiratory involement, as assisted
ventilation may be required. Patients may remit
permanently, however, especially after thymectomy or
with immunosuppressive treament.
 Oral acetylcholinesterases

Pridostigmine is most widely used drug, with a

duration of action of about 3-5 hours. The patient’s
response will determine the dosage required.

Overdosage causes a cholinergic crisis with sever

weakness, which may be difficult to differentiate from
the myasthenic weakness. Colic and diarrhoea may
also occur.
 Acetylcholines are excellent symptomatic
drugs but do not alter the natural history of the
disease.
 Thymectomy

In patients with thymic hyperplasia, thymectomy,

for unknown reasons, improves the prognosis of the
disease, especially in the under 40 years of age and in
those who have had the disease for less than 10 years.

In patient with a thymoma, surgery is essential to

remove a potentially malignant tumour, but it rarely
causes improvement of the myasthenia.
Immunosuppression

Corticosteroids provide the mainstay of

immunosuppressive treatment. They succeed in 70% of
patients, but must be increased slowly, preferably in
hospital, as there is often a temporary exacerbation of
symptoms before the therapeutic effect.

Plasmapheresis is sometimes used, especially during

an acute exacerbation or when there is respiratory
involvement. The effects only last a few days ,however.

Azathioprine is used as a steroid-sparing agent.

Lambert-eaton myasthenic syndrome

In LEMS, a rare condition, antibodies are directed

against the voltage-gated calcium channels. This results
in a failure of acetylcholine release from the presynaptic
nerve terminal. In many cases, it is a non-metastatic
manifestation of malignacy of a small-cell carcinoma of
the lung.
 It is characterized by weakness of the proximal
limb muscles and occasionally ptosis, but other
cranial nerves are typically spared. There may be
fatiguability but characteristically there is a
paradoxical improvement in power after exercise.
Reflexes are usually absent ,but these may return
following exersise.
 The diagnosis can be confirmed
electromyographically by an increment of the
compound muscle action potential after repetitive
stimulation. A search should be made for malignancy,
especially bronchial.

Guanethidine hydrochloride and 4-aminopyridine

may enhance acetylcholine release. Steroids and
plasmapheresis may also help. However , the prognosis
for those with a primary lung tumour is usually poor.