Botulinum toxin adverse effects

Clostridium botulinum, anaerobic gram positive bacteria, produces seven different types of toxins, named with alphabet letters from A to G.
In clinical practice (Table 1) only toxin A (Botox®, Vistabex®, Dysport®) and B (Neurobloc®) are used. These drugs contain a complex of real toxin and a non-toxic protein fraction to stabilize the compound. Botulinum toxin acts at the neuromuscular junction.
Synaptic vesicles containing acetylcholine fuse to the presynaptic membrane through a protein complex named SNARE. The fusion process allows acetylcholine release into the intrasynaptic space and consequent muscular fibers activation.
The toxin active-form consists of a 100-kDa heavy chain (H-chain) and a 50-kDa light chain (L-chain) joined by a disulfide. When injected in proximity of the neuromuscular junction, the toxin binds with high affinity to the vesicle protein SV2 and then enters the cell by endocytosis. Inside the cytoplasm of the presynaptic terminal, L-chain operates its proteolytic activity on the SNARE complex, which is involved in the synaptic vesicles fusion with the cellular membrane and in the consequent acetylcholine release. Different toxin serotypes act on different proteins into the SNARE complex, blocking it irreversibly. The result is the blockage of the cholinergic synapses with consequent muscular or glandular denervation. The nervous cell needs three months to synthesize and re-transport the complex SNARE proteins to the presynaptic terminal; after this period of time the synapse resumes its original functionality.
In 1989 the FDA approved the use of botulinum toxin type A for strabismus and blepharospasm. Later on, the toxin use was extended with more indications, in particular to hemifacial spasm, focal dystonia and localized hyperhidrosis. In Italy botulinum toxin type A has been authorized since 2004 for glabellar wrinkles treatment (see table 1).
Botulinum toxin vials must be kept refrigerated according to the manufacturer indications; they must be reconstituted with physiological solution and used within few hours (4-5 hours). Wrinkles and hyperhidrosis are treated by intradermal injections. The medication needs to be diluted in physiological solution, considering that high-dilutions might facilitate wider diffusion with consequent increased risks of adverse reactions and engagement of adjoining muscles. The usage of botulinum toxin for aesthetic dermatology requires deep knowledge of the anatomy and physiology of the facial musculature in order to avoid inesthetism.

Precautions and adverse effects

Patients affected by muscular pathologies should not receive botulinum toxin treatments (although this is not an absolute contraindication). Also patients on anticoagulant therapy are advised not to be treated because of the inevitably high number of injections. There are no studies on the toxin use in pregnancy and breastfeeding.
When treating palmar hyperhidrosis, a temporary reduction of prehension strength might occur. Transitory generalized asthenia and accommodation disturbances have also been occasionally reported after treatments with botulinum toxin at high dosage (300 U Botox®, 1,050 U Dysport®).
It is important to notice that the toxin use for aesthetic treatments is indicated only for glabellar wrinkles, i.e. the vertical ones over the eyebrows, “in patients over 65 years old, when the gravity of the wrinkles severely impacts the patient on a psychological level”. On the contrary, the usage of the toxin for any other aesthetic reasons – in particular in very delicate injections-sites like around the eyes, on the forehead, around the lips and on the neck – is off label and can expose patients to serious risks. For example botulinum administration around the mouth can compromise the mastication muscles function and create speech impairments.
In fact the toxin diffuses from the target muscles to other muscular groups, possibly leading to adverse reactions like palpebral ptosis, focal facial paralysis, paresthesia and numbness, asthenia, muscular weakness, dysphagia and visual disturbances.
According to a report from Italian Medicines Agency, more than thirty patients incurred into adverse reactions after treating glabellar wrinkles with botulinum toxin.

Table 1 – Commercial preparations, indications and uses