Abstract: The seven serotypes of botulinum toxin (BTX) produced by Clostridium botulinum exert their paralytic effect by inhibiting acetylcholine release at the neuromuscular junction. Each of these zinc endopeptidases cleaves one or more proteins involved in vesicle transport and membrane fusion. The extent of paralysis depends on both doses and volume; the duration of paralysis is further dependent on the serotype employed. Restoration of neuromuscular function follows axon terminal sprouting. The two major commercial preparations of BTX-A appear to differ in their relative potencies, despite a common unit labeling system. Adverse effects are a consequence of the drug's mechanism of action, and can usually be tolerated or mitigated through dosing changes. Patients who are pregnant or lactating, or who have a neuromuscular disease, may not be appropriate candidates for BTX therapy. Development of resistance to BTX-A therapy, characterized by absence of any beneficial effect and by lack of muscle atrophy following the injection, is an important clinical issue. The incidence of antibody-mediated resistance, as determined by the mouse lethality assay, is reported between 3% and 10%. Use of the smallest possible effective dose and longer treatement intervals may reduce the likelihood of antibody development. Other serotypes may benefit those who have developed antibody resistance.
BTX-A is approved in most countries for strabismus, blepharospasm, and focal spasms including hemifacial spasm
It is widely used and indicated for many cases of cervical dystonia, spasticity and other disorders of excess muscle activity
Like tetanus toxin, BTX is a zinc endopeptidase. Its seven serotypes differ in their cellular targets as well as their potency and duration of action
BTX is internalized by endocytosis at the axon terminal and becomes fully activated by disulfide reduction once inside the cell
BTX-A targets SNAP-25
The existence of retrograde transport of intact toxin has not been proven, and is unlikely to be clinically important
BTX-A causes reversible denervation atrophy
Axon sprouting terminates the clinical effect usually in 2-6 months
Extent of denervation is determined largely by dose and volume of injection
BOTOX&3174; and Dysport&3174; differ in their apparent unit potency
While at least one study finds no discrepancy, most have suggested the BOTOX&3174; unit is 3-5 times as potent as the Dysport&3174; unit
The lethal parenteral dose of BTX-A in humans is not known; it has been estimated to be nearly 3000 U
The maximum recommended dose per treatment session is 300-400 U
Antitoxin antibodies are presumed responsible for most cases of resistance
The mouse assay probably underestimates the prevalence of antibody-mediated resistance
The prevalence of neutralizing antibodies among patients receiving chronic treatment at the higher doses for torticollis or spasticity is probably at least 3%
Patients with BTX-A resistance may benefit from injections with other serotypes, including BTX-B, -C, and -F. Differences in duration of effect may be significant
To minimize immunoresistance:
use the smallest possible effective dose
extend the interval between treatment as long as possible, with at least 3 months between treatments
avoid using booster injections
Long-term effects of BTX-A are mild and may include changes in muscle fiber size and EMG abnormalities. These changes do not appear to have any clinical significance
Isolated cases have been reported of gall bladder attack, urinary incontinence, brachial plexopathy, and generalized botulism-like syndrome
BTX is generally contraindicated in pregnancy, lactation, and neuromuscular disease, though there are cases of uncomplicated therapy in some of these conditions
Fig. 1
The botulinum toxin molecule is synthesized as a single chain and then cleaved to form the dichain molecule with a disulfide bridge. The light chain (amino acids 1-448) acts as a zinc endopeptidase, with proteolytic activity concentrated at the N-terminal end. The heavy chain (amino acids 449-1280) provides cholinergic specificity and promotes light chain translocation across the endosomal membrane.
Fig. 3
Synaptosomal vesicle fusion requires the interactions of more than half a dozen different proteins. As shown in the figure, the various serotypes of BTX target at least three of these proteins: VAMP/synaptobrevin, SNAP-25, and syntaxin.
Fig. 4
Botulinum toxin causes reversible denervation atrophy. Histological evidence shows that reinnervation may occur through noncollateral sprouting from the unmyelinated terminal axon immediately proximal to the end plate, as shown. Additional sites of sprouting are the nodes of Ranvier of myelinated parent preterminal axons and the ultraterminal axonal arborization over the end plate (not shown).
