130 MOVEMENT DISORDERS AND DEGENERATIVE CNS DISEASE
Key points
Myasthenia gravis- Auto-antibodies to nicotinic acetylcholine receptors
lead to increased receptor degradation and
neuromuscular blockade. - Treatment is with an oral anticholinesterase (e.g.
neostigmineorphysostigmine). Over- or
under-treatment both lead to increased
weakness (‘cholinergic’ and ‘myasthenic’ crises,
respectively). - Cholinergic and myasthenic crises are differentiated by
administering a short-acting anticholinesterase,
intravenousedrophonium. This test transiently
improves a myasthenic crisis while transiently
worsening a cholinergic crisis, allowing the appropriate
dose adjustment to be made safely. - Immunotherapy with azathioprineand/or corticosteroids
or thymectomy may be needed in severe cases. - Weakness is exacerbated by aminoglycosides or
erythromycinand patients are exquisitely sensitive to
non-depolarizing neuromuscular blocking drugs (e.g.
vecuronium).
potential, thus reducing the force of contraction of the muscle.
The precise stimulus for the production of the antireceptor anti-
bodies is not known, although since antigens in the thymus
cross-react with acetylcholine receptors, it is possible that these
are responsible for autosensitization in some cases.
Diagnosis is aided by the use of edrophonium, a short-acting
inhibitor of acetylcholinesterase, which produces a transient
increase in muscle power in patients with myasthenia gravis.
The initial drug therapy of myasthenia consists of oral anti-
cholinesterase drugs, usually neostigmine. If the disease is
non-responsive or progressive, then thymectomy or immuno-
suppressant therapy with glucocorticosteroids and azathioprine
are needed. Thymectomy is beneficial in patients with associated
thymoma and in patients with generalized disease who can with-
stand the operation. It reduces the number of circulating T-lym-
phocytes that are capable of assisting B-lymphocytes to produce
antibody, and a fall in antibody titre occurs after thymectomy,
albeit slowly. Corticosteroids and immunosuppressive drugs
also reduce circulating T cells. Plasmapheresis or infusion of
intravenous immunoglobulin is useful in emergencies, produc-
ing a striking short-term clinical improvement in a few patients.
ANTICHOLINESTERASE DRUGSThe defect in neuromuscular transmission may be redressed by
cholinesterase inhibitors that inhibit synaptic acetylcholine
breakdown and increase the concentration of transmitters avail-
able to stimulate the nictonic receptor at the motor end plate.
Neostigmineis initially given orally eight-hourly, but usu-
ally requires more frequent administration (up to two-hourly)
because of its short duration of action (two to six hours). It is
rapidly inactivated in the gut. Cholinesterase inhibitors
enhance both muscarinic and nicotinic cholinergic effects. The
former results in increased bronchial secretions, abdominal colic,
diarrhoea, miosis, nausea, hypersalivation and lachrymation.
Excessive muscarinic effects may be blocked by giving
atropineorpropantheline, but this increases the risk of over-
dosage and consequent cholinergic crisis.
Pyridostigminehas a more prolonged action than neostig-
mineand it is seldom necessary to give it more frequently than
four-hourly. The effective dose varies considerably between
individual patients.
ADJUVANT DRUG THERAPY
Remissions of myasthenic symptoms are produced by oral
administration of prednisolone. Increased weakness may occur
at the beginning of treatment, which must therefore be instituted
in hospital. This effect has been minimized by the use of alter-
nate-day therapy. Azathioprine(see Chapter 50) has been used
either on its own or combined with glucocorticosteroids for its
‘corticosteroid-sparing’ effect.
MYASTHENIC AND CHOLINERGIC CRISISSevere weakness leading to paralysis may result from either a
deficiency (myasthenic crisis) or an excess (cholinergic crisis)
of acetylcholine at the neuromuscular junction. Clinically, the
distinction may be difficult, but it is assisted by the edropho-
niumtest.
Edrophonium, a short-acting cholinesterase inhibitor, is
given intravenously, and is very useful in diagnosis and for dif-
ferentiating a myasthenic crisis from a cholinergic one. It tran-
siently improves a myasthenic crisis and aggravates a cholinergic
crisis. Because of its short duration of action, any deterioration of
a cholinergic crisis is unlikely to have serious consequences,
although facilities for artificial ventilation must be available. In
this setting, it is important that the strength of essential (respira-
tory or bulbar) muscles be monitored using simple respiratory
spirometric measurements (FEV 1 and FVC) during the test,
rather than the strength of non-essential (limb or ocular) muscles.
Myasthenic crises may develop as a spontaneous deteriora-
tion in the natural history of the disease, or as a result of infection
or surgery, or be exacerbated due to concomitant drug therapy
with the following agents:- aminoglycosides (e.g. gentamicin);
- other antibiotics, including erythromycin;
- myasthenics demonstrate increased sensitivity to non-
depolarizing neuromuscular-blocking drugs; - anti-dysrhythmic drugs, which reduce the excitability of
the muscle membrane, and quinidine(quinine),
lidocaine,procainamideandpropranolol, which may
increase weakness; - benzodiazepines, due to their respiratory depressant
effects and inhibition of muscle tone.
TREATMENT
Myasthenic crisis
Myasthenic crisis is treated with intramuscular neostigmine,
repeated every 20 minutes with frequent edrophoniumtests.
Mechanical ventilation may be needed.