There has been considerable progress in understanding the mechanism of
action of the toxin . The main site of action is the neuromuscular
junction, where the toxin binds rapidly and prevents the release of
acetylcholine. The reason that it is possible to produce sufficient weakness
of the muscle to prevent symptomatic spasm, but not completely block
voluntary control, may be that more active neuromuscular junctions are more
likely than less active junctions to be blocked. The toxin may also have
some action on the central nervous system. For example, the spinal cord
process of reciprocal inhibition is deficient in focal hand dystonia and
normalizes with treatment, although this finding may be due to peripheral
mechanisms.
Botulinum toxin A is the only type currently marketed, but there is
considerable interest in other serotypes. One of the reasons is that
antibodies to type A develop in as many as 10 percent of patients,
particularly after large repeated doses, and then such patients become
completely resistant to further treatment with this serotype. Botulinum
toxin B has been studied in patients with spasmodic torticollis and may
reach the market soon. Its action is similar to that of type A, and it can
be effective in cases in which there are antibodies to type A. Type F can
also be effective in patients with antibodies to type A. Its duration of
action, however, is approximately half that of type A, and hence it would be
less desirable for chronic conditions. On the other hand, it might be
preferable for conditions such as chronic anal fissure, for which a short
duration of action would be beneficial.
The dose of botulinum toxin is measured in functional units corresponding to
the median lethal dose for female Swiss Webster mice weighing 18 to 20 g.
Doses range widely, depending on the size of the muscle, the degree of
weakness required, and the commercial preparation of the toxin. Since the
toxin diffuses into the tissue, local side effects can occur with low doses,
but the rare systemic side effects occur only with doses of several hundred
units.
The local side effects of botulinum toxin are generally limited to weakness
of the injected muscles or other nearby muscles. Typically, the excessive
weakness will last only one to two weeks. After injection of the vocal cords
for spasmodic dysphonia, for example, the voice may become breathy and there
may be mild difficulty with swallowing. Systemic side effects are uncommon.
Although single-fiber electromyographic studies indicate that neuromuscular
junctions are affected throughout the body, generalized weakness is rarely
seen. Typically asymptomatic autonomic side effects demonstrable by
quantitative testing include sluggishness of pupillary responses, a
reduction in the variability of the heart rate, and impaired emptying of the
gall bladder.
Experience with botulinum toxin indicates that conditions that affect the
central nervous system can be treated successfully, if only symptomatically,
with a peripheral agent. If used carefully, botulinum toxin has minimal side
effects, and patients can reap a wide range of benefits. Because the
duration of action of the toxin is limited, however, treatment often must be
given about every three months. A goal for the future is the development of
similar agents with longer durations of action.
Mark Hallett, M.D.
National Institutes of Health
Bethesda, MD 20892-1428
http://www.nejm.org/
Copyright © 1999 by the Massachusetts Medical Society.
--
Judith Richards, London, Ontario, Canada
[log in to unmask]
^^^
\ /
\ | / Today’s Research
\\ | // ...Tomorrow’s Cure
\ | /
\|/
```````
