The Multispecialty Toxin: A Literature Review of Botulinum Toxin

Karen Bach, BS; Richard Simman, MD, FACS, FACCWS

Disclosures

Plast Reconstr Surg Glob Open. 2022;10(4):e4228 

In This Article

Methods

A literature review was conducted in the PubMed database limited to English language articles published using the terms: "Botulinum Toxin," "Botulinum Neurotoxin," "Botulinum Toxin A," "Botox" in various combinations with "Ophthalmology," "Neurology," "Plastic Surgery," "Dermatology," "Gastrointestinal," "Urology," "Gynecology," "Rheumatology," "Orthopedics," "clinical applications," "dose," and "complications." Articles describing the use of botulinum toxin were selected, reviewed, and summarized in this article. References from each article were also reviewed for additional relevant articles.

Historical Review

Historically, the idea of using BoNT therapeutically originated from Justinus Kerner in the early 1800s. He referred to the toxin as "sausage poison" after noting its effects following ingestion of spoiled smoked blood sausages. In 1870, John Muller coined the term "botulism" (the Latin root botulus means "sausage") and in 1895, van Ermengem isolated the bacterium for the first time.[2,3] The discovery of the bacterium and toxin led to the investigation of its use as a treatment for strabismus.[3,4] Finally, in 1989, it was FDA approved as a therapy for strabismus, blepharospasm, and hemifacial spasm.[5,6] In 2000, it was FDA approved for the treatment of cervical dystonia.[7,8] Since then, it has been widely accepted and utilized for both on- and off-label by multiple medical specialties for a variety of conditions (Figure 1).

Figure 1.

Historical timeline of BoNT and its FDA approvals.

Mechanism of Action

BoNT is synthesized as an inactive 150-kDa single chain polypeptide, which undergoes cleavage, and thus activation, by trypsin or bacterial enzymes into a 100 kDa heavy chain and 50 kDa light chain.[9] BoNT selectively and reversibly binds in the presynaptic terminal of the neuromuscular junction to specific membrane protein complexes called SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) to prevent the release of acetylcholine.[10,11] BoNT type A and E cleave the SNARE component SNAP-25 (synaptosomal associated protein),[12,13] while type C cleaves both SNAP-25 and syntaxin.[14] Type B, D, and F cleave the SNARE component synaptobrevin (vesicle-associated membrane protein or VAMP).[13,15] Without the presynaptic release of acetylcholine, muscle contraction cannot occur, leading to its many beneficial uses in disorders with abnormal, excessive, or inappropriate muscle contractions.

Commercially Available Formulations of BoNT

Several FDA-approved commercial formulations of BoNT (Botox, Dysport, Xeomin, Jeuveau, Myobloc/Neurobloc) are available in the United States. Each product differs in pharmaceutical form, units per vial, molecular weight, expedients used for preparation, onset of action, dosing, storage, and FDA-approved indications. A comparison of these properties is provided in Table 1. Due to the distinct pharmacological properties of the formulations, these agents should not be used interchangeably.

General Complications

The effects of BoNT are temporary, taking effect within 24–72 hours and lasting anywhere between 3 and 6 months depending on patient-specific factors, indications, and dosage. Dosing can be expressed in terms of international units, where 1 international unit corresponds to the median lethal dose (LD50) to kill 50% of a colony of mice by intraperitoneal injection. The LD50 for humans is approximately 0.8–0.9 μg by inhalation, 30 ng by ingestion, and 0.09–0.15 μg by intravenous route.[16] Notably, potency Units (U) are specific to each BoNT preparation and thus, are not interchangeable. Treatment is generally safe and well-tolerated by patients when used appropriately; however, a small subset of patients can experience side effects.[17] In most cases, the side effects are localized and self-limiting, such as erythema, edema, bruising, and pain. Systemic complications are rare and severe adverse effects, such as muscle weakness and allergic reactions, tend to be dose-dependent, with the frequency being 33 times higher for therapeutic cases than for cosmetic cases, and can be exacerbated if patients have a history of multiple treatments at the same site within a narrow time interval or concomitant neuromuscular junction disorders.[18] As with any procedures that breach the skin barrier, infections are also a possibility. Management of complications tends to focus on symptomatic treatment. Specific complications of BoNT and any antidotal treatment will be further discussed in the sections below according to their use indications.

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