USE OF BOTULINUM TOXIN AS A MUSCLE

RELAXANT
Injection of botulinum toxin is a rather innovative way to control localized muscle
hyperexcitability. Botulinum toxin is a purified version of the toxin that causes
botulism.

Systemic doses of this toxin can be extremely dangerous or fatal because botulinum
toxin inhibits the release of acetylcholine from presynaptic terminals at the skeletal
neuromuscular junction. Loss of presynaptic acetylcholine release results in paralysis of
the muscle fiber supplied by that terminal.

Systemic dissemination of botulinum toxin can therefore cause widespread

paralysis, including loss of respiratory muscle function.

Injection into specific muscles, however, can sequester the toxin within these muscles,
thus producing localized effects that are beneficial in certain forms of muscle
hyperexcitability.

MECHANISM OF ACTION.
The cellular actions of botulinum toxin at the neuromuscular junction have recently
been clarified. This toxin is attracted to glycoproteins located on the surface of the
presynaptic terminal at the skeletal neuromuscular junction.

Once attached to the membrane, the toxin enters the presynaptic terminal and inhibits
proteins that are needed for acetylcholine release (Figure 13–4).
Normally, certain proteins help fuse presynaptic vesicles with the inner surface of the
presynaptic terminal, thereby allowing the vesicles to release acetylcholine via
exocytosis. Botulinum toxin cleaves and destroys these fusion proteins, thus making it
impossible for the neuron to release acetylcholine into the synaptic cleft.

Local injection of botulinum toxin into specific muscles will therefore decrease muscle
excitation by disrupting synaptic transmission at the neuromuscular junction. The
affected muscle will invariably undergo some degree of paresis and subsequent
relaxation because the toxin prevents the release of acetylcholine. It has been
suggested that botulinum toxin might have other effects on neuronal excitability.

CLINICAL USE OF BOTULINUM TOXIN.

Seven strains (serotypes) of botulinum toxin have been identified, but only two
types are currently available for clinical use: botulinum toxin types A and B.

These types differ somewhat in their chemistry, duration of action, and so forth.

The most commonly used therapeutic type is botulinum toxin type A; this agent is
marketed commercially under trade names such as Botox and Dysport.

Botulinum toxin type B (Myobloc) is also available, and can be useful in patients who
develop immunity to the type A form of this toxin (discussed later). Botulinum toxin
has been used for some time to control localized muscle dystonias, including conditions
such as spasmodic torticollis, blepharospasm, laryngeal dystonia, strabismus, and
several other types of focal dystonias. When used therapeutically, small amounts of this
toxin are injected directly into the dystonic muscles, which begin to relax within a few
days to 1 week. This technique appears to be fairly safe and effective in many patients,
but relief may only be temporary. Symptoms often return within 3 months after each
injection, necessitating additional treatments. Still, this technique represents a method
for treating patients with severe, incapacitating conditions marked by focal dystonias
and spasms. More recently, there has been considerable interest in using botulinum
toxin to reduce spasticity in specific muscles or muscle groups. This treatment has been
used to treat spasticity resulting from various disorders including cerebral palsy
traumatic brain injury, CVA, and spinal cord injury.

LIMITATIONS AND SIDE EFFECTS.

Botulinum toxin does not cure spasticity and there are a number of limitations to
its use. In particular, only a limited number of muscles can be injected during a given
treatment because only a limited amount of botulinum toxin can be administered during
each set of injections. For example, the total amount of botulinum toxin type A
injected during each treatment session is typically between 200–300 units in
adults, with proportionally smaller amounts used in children depending on his or her
size and age.

 The typical dose of the type B form is 2500–5000 units. Exceeding these
doses will cause an immune response whereby antibodies are synthesized
against the toxin, making subsequent treatments ineffective because the
patient’s immune system will recognize and inactivate the toxin. The number of
muscles that can be injected is therefore often limited to one or two muscle
groups; for example, the elbow and wrist flexors in one upper extremity of an
adult, or the bilateral triceps surae musculature of a child. As indicated earlier,
the relaxant effects of the toxin are likewise temporary, and these effects typically
diminish within 2 to 3 months after injection.91
 The effects apparently wear off because a new presynaptic terminal “sprouts”
from the axon that contains the originally affected presynaptic terminal. This new
terminal grows downward, reattaching to the skeletal muscle and creating a new
motor end plate with a new source of acetylcholine. The effects of the previous
injection are overcome when this new presynaptic terminal begins to function..
Botulinum toxin can therefore be used as part of a comprehensive
rehabilitation program to provide optimal benefits in certain patients with
severe spasticity