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1. From Poison to Remedy

Botulism presents a clinical picture characterized by symmetrical cranial nerve palsies followed by descending, symmetric flaccid paralysis of voluntary muscles, which may progress to severe respiratory failure and death ^[1]. There are four main forms: food-borne, wound, infant botulism, and adult intestinal toxemia. The mechanism of action of botulinum toxins was described as follows. When botulinum toxin lost its medullary sheath on entry into the endplate, it was irreversibly fixed to the fine nerve fibers. Consequently, no release of acetylcholine took place, and then the transmission of the impulse through those fibers was abolished, resulting in the observed neuro-muscular block. It was also found that a much higher dose of toxin B than toxin A was required to achieve the same paralyzing effect ^[2].

The first therapeutic use of botulinum toxin was reported by ophthalmologist Alan Scott to treat strabismus in 1973 ^[3]. Later, it began to be used in dystonia, such as hemifacial spasm or torticollis. In 1989, the FDA approved the indication of BoNT/A for the treatment of blepharospasm, and in the 1990s, the indication for cerebral spasticity (stroke and cerebral palsy) was approved too. Its use in cosmetics and other indications, such as hiperhidrosis, is already recognized. For this reason, since the late 1980s, the main research has focused on the mechanisms of action of botulinum toxins for therapeutic use and the development of new safer and more potent types and formulations of toxins and new therapeutic indications ^[4].

2. Therapeutic Use for Botulinum Neurotoxins

2.1. Current Botulinum Neurotoxin Formulations

Currently, there are clinical trials to investigate whether BoNT/F or BoNT/A2 could be used as therapy in humans. BoNT/A2 has been proven to be more effective than BoNT/A1 at 30 days of injection and less likely to have unintended effects at a distance ^[5]. However, the presentations marketed now are almost all based on BoNT/A1 and one on BoNT/B1.

OnabotulinumtoxinA (ONA) and AbobotulinumtoxinA (ABO) are purified PTC containing BoNT/A1 (pharmacologically active ingredient), NTHTA, and the HA proteins. ONA is a 900 kDa complex marketed as a vacuum-dried powder for reconstitution; it remains usable at 2–8 °C for 36 months. ABO is an 800 kDa complex marketed as a freeze-dried powder for reconstitution, and it remains usable at 2–8 °C for 24 months. IncobotulinumA (INC) contains only the purified BoNT/A1, is a 150 kDa molecule marketed as a freeze-dried powder for reconstitution, and remains usable at room temperature for 36 months. RimabotulinumtoxinB is the only presentation of BoNT/B1, is a 320 kDa molecule, is marketed as a ready-to-use solution, and remains usable at 2–8 °C for 24 months.

2.2. Clinical Applications

Dystonia. BoNTs can significantly temporarily relieve sustained contractures and repetitive twisting movements, constituting the first-choice treatment for most dystonia ^[6]. BoNT/A treatment of blepharospasm was approved by the FDA in 1989. Cervical dystonia is the only official indication for BoNT/B.

Spasticity. It is defined as a “disordered sensorimotor control, resulting from an upper motor neuron lesion, presenting as intermittent or sustained involuntary activation of muscles” ^[7]. It is the most important indication of central nervous system (CNS) disorders. Its efficacy was demonstrated in the early 1990s, although traditionally evidence had only been found that it is effective when used in patients with stroke or infantile cerebral palsy (CP), or for the treatment of hip adductors in patients with multiple sclerosis, and for this reason, these are the only diseases causing spasticity which have treatments approved by the FDA ^[8][9]. Furthermore, in almost all clinical guidelines for the treatment of CP or post-stroke spasticity, oral antispastic medication is not allowed, and, therefore, the only drug we can use is BoNT. Spasticity caused by other disorders can be treated with BoNTs, although it does not have an official indication, but, in general, it is recommended only if the distribution is focal ^[10][11]. The discovery of toxin’s retrograde axonal transport to CNS might suggest additional action sites, which in this case would be central (apart from directly injected muscle fibers) but is not yet well studied ^[12].

Other disorders of the CNS. Neurogenic detrusor overactivity, usually due to spinal cord injury (SCI), is a treatment indication approved by the FDA since 2011 and supported by clinical trials ^[13]. BoNT can also be used to relax trismus or bruxism secondary to brain damage ^[14].

Autonomic disorders. BoNT/A has an approved indication for the treatment of severe and persistent primary hyperhidrosis of the axilla ^[15].

Other urologic disorders. BoNT can be applied in painful bladder or cystitis ^[16] and for the treatment of urethral sphincter alterations, sphincter pseudodysynergia, or obstructive syndromes ^[17].

Peripheral facial paralysis. BoNT/A can be used to regain facial symmetry both at rest and during voluntary movement and as a treatment for synkinesis ^[18].

Pain. The only approved indication for BoNT is chronic migraine, where it acts by interfering with peripheral and possibly central sensitization, and its main role is the block of vasoactive peptides release from trigemino-vascular endings ^[19]. BoNT has been used successfully in neuropathic pain, mainly of peripheral origin (postherpetic neuralgia, diabetic neuropathy) ^[20]. It can also be used to treat myofascial pain, temporomandibular disorders, low back pain, Arnold occipital neuralgia and tension neck pain, and idiopathic or dental bruxism ^[21].

Aesthetics. Cosmetic use has become the most popular application, and there are specific presentations of each formulation for this indication.

Spasticity in Spinal Cord Injury. Spasticity could be treated in a standard way regardless of the etiology, but there are differences if the cause is cerebral or spinal [52]: As spasticity following SCI is usually generalized over the whole body, the recommended treatments are those that can correct all the affected muscles. The most important systemic treatments include oral medication (baclofen, tizanidine) and patient education (knowledge of the most frequent factors that cause a worsening of their spasticity and the times when there may be functional
interference) [54,55]. If we wanted to treat the spasticity of SCI with BoNT, we would need very high doses for many several muscles, which would require an intolerable total concentration. Furthermore, there is no official indication of BoNT in spasticity of SCI. These two facts would make us think that we cannot or should not use BoNT in SCI. Some BoNT indications yet not approved by official drug agencies are contained in an international agreement, but SCI-related spasticity is not included [33]. However, a panel of experts in SCI spasticity within the International Spinal Injury Society (ISCoS) called Ability Network, have made several recommendations in the treatment of SCI spasticity, and among them is the use of BoNT/A as complementary to the rest of the treatments of which the most important is
patient education and oral drugs [55].The indications are based on the protocols and guidelines published to date: focal spasticity, muscles with worse functional disadvantages. and adjuvant therapy.

2.3. Adverse Effects and Other Considerations

The overall rate of possible adverse effects is minimal; effects related to the injection itself (infection, bruising, bleeding) are rare when the injector is skilled and experienced. The possibility of local diffusion or even leakage into the systemic circulation with distal effects has been described. Muscle weakness or loss of function may be found due to paralysis of the target organ we are injecting ^[22]. The possibility of allergic or hypersensitivity reactions has been described but are extremely rare.

The repeated injection of BoNT can maintain and even increase the beneficial effects over time ^[23], for which a chronic treatment, typical in dystonia, migraine, and spasticity, could be justified. However, there is a potential danger of local effects after repeated injections, such as those seen in the treatment of overactive bladder, where patients no longer responding to BoNT treatment displayed a significant increase in the afferent terminals, likely excitatory, and signs of chronic neurogenic inflammation in the mucosa ^[24].