Clostridium botulinum, an anaerobic, rod-shaped bacterium, produces a neurotoxin called botulinum toxin (BoNT) during sporulation [1,2,3]. BoNT is the most potent biological toxin, as it causes botulism manifested by paralysis of muscles and eventual fatal respiratory failure [4,5]. When an action potential arrives at the cholinergic presynaptic nerve terminal, there is an influx of calcium into the presynaptic terminal, which then facilitates acetylcholine vesicle fusion with the presynaptic membrane; this fusion is facilitated by a group of proteins referred to as SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor) proteins, which include SNAP 25 (25 kD synaptosomal-associated protein) and Syntaxin [6,7]. BoNT acts at the cholinergic presynaptic nerve terminal by cleaving and inactivating SNARE proteins, thus inhibiting release of acetylcholine, which in turn prevents muscle contraction and results in local weakness and paralysis [7,8]. BoNT acts at both the extrafusal and intrafusal muscle fibers, thereby preventing contraction of both agonist and antagonist muscles [8,9]. This biologic effect of BoNT has been turned into an advantage in patients troubled by involuntary muscle contractions, excessive secretions, pain, and other conditions [7]. The paralytic effects of BoNT were initially described in 1817 by Justinus Kerner, a German physician, who suggested that the toxin may be potentially useful in the treatment of St. Vitus’ dance, hypersalivation, and hyperhidrosis [10]. The mechanism of action of BoNT injections to account for the typical 3–4 months of duration has not been fully elucidated, and the original proposal that axonal sprouting occurs at the presynaptic nerve terminal after the injection, after which time the neuromuscular junction integrity is restored when the original nerve terminals regain their exocytic function, hence necessitating repeat injections [11], has been challenged [12].

In 1981, Dr. Jankovic initially injected BoNT into a patient for treatment of blepharospasm (BSP) [10] and subsequently published the results of the first double-blind, placebo-controlled trial of BoNT in cranial–cervical dystonia [13]. The results of this trial, along with additional data, were used by the United States Food and Drug Administration (FDA) to approve BoNT in 1989 for the treatment of BSP and facial nerve disorders such as hemifacial spasm (HFS) [14]. Although only BoNT types A and B have been approved for clinical use by the FDA, there are a total of eight different subtypes: BoNT A to H [6].

There are currently four FDA approved BoNT formulations: the three types of botulinum toxin type A (BoNTA) available are onabotulinumtoxinA (Botox; Allergan, CA, USA), abobotulinumtoxinA (Dysport; Ipsen-Pharma, UK), and incobotulinumtoxinA (Xeomin; Merz Pharma, Germany); rimabotulinumtoxinB (Myobloc in the USA; Supernus Pharmaceuticals, Inc, Rockville, MD; Neurobloc in Europe, Sloan Pharma, Switzerland) is a BoNTB preparation [6,10].

There are several BoNT preparations that are currently in development but have not yet been approved by the FDA. DaxibotulinumtoxinA is a novel BoNTA preparation that was recently evaluated in a phase 3 trial (ASPEN-1) in cervical dystonia (https://www.businesswire.com/news/home/20201014005360/en/). This study enrolled 301 patients from 60 sites in the U.S., Canada, and Europe and confirmed the findings of an earlier phase 2 study [15] in that it found that daxibotulinumtoxinA is safe and effective. Interestingly, at doses of 125 U, it has a median duration of effect (based on the median time to loss of 80% of the peak treatment effect) of 24 weeks. This relatively long duration of action offers potential advantage over other formulations in that it may allow increasing the intervisit interval beyond the conventional 3–4 months. LanbotulinumtoxinA (Prosigne; Shanghai, China) is a new preparation of BoNTA marketed chiefly in Asia [16,17].

The doses of different formulations are not interchangeable, but based on prior studies, the following ratios are often used in clinical practice when switching from one to another BoNT product to achieve similar results: onabotulinumtoxinA:incobotulinumtoxinA = 1:1; onabotulinumtoxinA:abobotulinumtoxinA = 1:2.5, and onabotulinumtoxinA:rimabotulinumtoxinB = 1:50 [10].

With long term use of BoNT, there is a risk of developing neutralizing antibodies (NAbs) [18], and patients may stop responding to BoNT. Factors that increase the risk of developing resistance to BoNT include a high protein load in some formulations, large individual and cumulative doses of BoNT, and short intervisit intervals, especially booster injections [18,19,20,21,22,23]. Immunogenicity varies among the different products and has been reported as low as 0% for incobotulinumtoxinA and as high as 42.4% for rimabotulinumtoxinB [20]. Brin et al. [23] noted a 1.2% frequency of NAbs based on mouse protection assay (MPA) in patients treated for cervical dystonia with onabotulinumtoxinA. In contrast, Albrecht et al. [18] reported a prevalence of 14% of NAbs in 596 treated with BoNTA, mostly abobotulinumtoxinA, for a mean of 5.3 years based on mouse hemidiaphragm assay (MHDA). Since biological assays such as MPA and MHDA are difficult to perform and they involve sacrificing animals, there is a huge unmet need to develop a simple, inexpensive, sensitive, and specific test for BoNT-blocking antibodies. If a patient reports lack of improvement (less than 25%) after at least two or three consecutive treatment visits, this raises a high level of suspicion of immunoresistance [20]. In this case, unilateral brow injection may be performed as a clinically useful test [20]. This involves injection of BoNT in the right medial eyebrow and reassessing in 1–2 weeks for paralysis of the right procerus/corrugator as manifested by asymmetric frowning, which would disprove immunoresistance [20]. We have not included spasticity in this article, as we believe it is beyond the scope of this review. The reader is referred to some recent reviews on this topic [24,25,26].

Our manuscript provides a comprehensive review of botulinum toxin in movement disorders. Figure 1 depicts the variety of movement disorders where botulinum toxin is used for therapeutic purposes.