Botulinum Toxin Injections

Structure and Serotypes

Q60.1 Clostridium botulinum produces seven known serologically distinct and immunologically independent neurotoxins, serotyped A, B, C, D, E, F, and G. The serotypes have different pharmacological characteristics, but all produce inhibition of acetylcholine (ACH) neurotransmitter release from the neuromuscular junction (NMJ), leading to flaccid muscle paralysis. All BoNT serotypes have a generally conserved small core neurotoxin protein (150 kDa), which is usually noncovalently bound to larger, nontoxic proteins that provide protection against the acidic environment of the gut and the degradative effects of intestinal proteases ( Fig. 60.1 ). During systemic intoxication in botulism, the BoNT complex reaches the bloodstream and the interaction between the hemagglutinin components of the accessory proteins and erythrocytes likely causes the toxic subunit to dissociate from its protein partners and become free to exert its toxic effect. The toxin’s heavy chain (HC) binds to the presynaptic nerve terminal and ultimately allows the light chain to enter the cytosol and cleave proteins required for ACH release. Neurotoxin types C and D have little effect on humans. Serotype A (BoNTA) is the most potent and longest lasting, which is why it was the first commercially available for medical use.

Recent studies using serotype E have yielded interesting results. It appears to have a rapid onset of approximately 24 hours, and a short duration of approximately 30 days. This has advantages for those who want to try neurotoxin but are afraid they may not like it. There may also be a role for serotype E in the reduction of postoperative pain and prevention of postoperative scarring.

Physiology of Nerves

In each motor nerve ending there are small intracellular lipid vesicles containing neurotransmitters such as ACH. When an action potential reaches the nerve ending the voltage change, or depolarization, stimulates calcium influx, which triggers the vesicles to move toward the plasma cell membrane where they dock, fuse, and release their contents into the synaptic cleft ( Figs. 60.2 and 60.3 ). The ACH binds to receptors on the postsynaptic muscle, which initiates muscular contraction. ACH exocytosis is extremely fast, occurring within less than 1 ms after excitation.

The vesicles are able to dock and fuse with the membrane thanks to the help of a group of proteins known as SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors), collectively referred to as the synaptic fusion complex. SNARE proteins that are found on the synaptic vesicle are termed v-SNARE and those on the neuronal presynaptic membrane are referred to ast-SNARE. SNARE proteins are critical components of the machinery that is believed to mediate all types of intracellular membrane fusion.

Mechanism of Action

Botulinum A Toxin Product Details

Q60.6 Most research and experience with BoNT has been with the Botox formulation, now also known by its nonproprietary name onabotulinumtoxin A, which was the first BoNTA approved for dermatologic use in North America. Presently there are three BoNTA products approved in the US. Unless otherwise stated, practical use of BoNT will refer to onabotulinumtoxin A (see Table 60.1 ). BoNTA vials can be heat sensitive so onabotulinumtoxin toxin A and abobotulinumtoxin A are to be stored either in the freezer or in a refrigerator, whereas incobotulinumtoxin A may be stored at 20°C to 35°C ( Table 60.2 ). The manufacturer recommends reconstitution with 0.9% sterile preservative-free saline; however, randomized controlled trials (RCT) have documented reduced pain when using saline preserved with benzyl alcohol, without loss of efficacy or added safety concerns. Reconstituted vials should be handled with care, although reports have shown no loss of efficacy if shaken. The product monographs in North America suggest use within 24 hours of reconstitution for Botox and Xeomin, and within 4 hours for Dysport. This timing is to ensure sterility, whereas in practice, use several weeks after reconstitution has been tested without loss of efficacy for Botox. Reconstitution volumes vary depending on the site, indication, and physician preference. Dosing is always measured in BoNT units, regardless of the volume of solution. Larger volumes may provide greater diffusion of the toxin, which is beneficial if large areas are to be treated, for example in hyperhidrosis of the axillae, but can be a disadvantage when vital structures are nearby, such as around the eye.

Three main areas of controversy related to the comparison of different BoNTA formulations are: dosing equivalence, diffusion patterns, and time of onset. Few studies have compared Dysport with Botox or Xeomin in a rigorous fashion. Efficacy, dosing, and diffusion patterns appear to be similar for Botox and Xeomin (see Table 60.1 ). Dysport appears to diffuse over slightly longer distances than Xeomin or Botox, but this may be related to inconsistent dosages used for comparison. Studies have suggested onset of action as early as 1 to 3 days with all three formulations.

Topical Botulinum Toxin A

Topical formulations of botulinum toxin type A have been evaluated in RCT for the management of lateral canthal lines and hyperhidrosis. Although some reports are promising, further research is still needed required.