Do the unintended actions of botulinum toxin at distant sites have clinical implications?

Abstract

Over the past 2 decades, botulinum toxin (BT) has enjoyed phenomenal success as a safe and effective therapeutic tool for neurologic and non-neurologic conditions. Even though recent evidence-based conclusions are limited by the availability of data, clinicians' practice confidently recommends BT for many clinical conditions. Besides being effective, BT injected locally has also been considered safe, because no evidence showed that the toxin acts also at distant sites. Recent findings from basic scientific research now challenge this conviction and raise concern that the toxin may have a less localized function than previously thought. Studies in rodents show that the toxin is retrogradely transported and even transcytosed to second-order neurons in the CNS. We therefore need to reappraise whether BT injected into muscles, glands, or cutis might induce previously unconsidered central actions, and whether these actions might have clinical implications. In eliciting clinical benefits, BT's peripheral and central action probably summate. Whether BT acts centrally mainly through retrograde transport, transcytosis, or both remains unclear. Whatever the mechanism, the lack of deleterious central effects implies that while research into action mechanisms continues, physicians can safely use BT for therapy.

Serious and Long-Term Adverse Events Associated with the Therapeutic and Cosmetic Use of Botulinum Toxin

“…These adverse events may be fatal if left untreated. Additionally, experimental studies in rodents have shown that botulinum toxin receptors exist in the central nervous system and a small amount of botulinum toxin crosses the blood-brain barrier [53]. This raises the possibility that botulinum toxin is transported retrogradely, similar to tetanus toxin, and may cause centrally mediated side effects.…”

Central origin of the antinociceptive action of botulinum toxin type A

“…From a clinical point of view, these findings raise the question whether BTX-A injected into muscles or cutis might induce unexpected central actions, and whether these actions might have clinical relevance (Currà and Berardelli, 2009). …”

Effects of botulinum toxin type A facial injection on monoamines and their metabolites in sensory, limbic and motor brain regions in rats

“…Also, studies in humans support the idea that BTX-A injected at therapeutic doses induces distant spinal and cortical effects indirectly by promoting brain changes due to plastic rearrangements subsequent to denervation or alterations in sensory input [22]. An excellent clinical example is that BTX injected into the affected muscles in patients with cervical dystonia relieves pain [10]. In addition, possible direct central actions mediated through toxin axonal transport from periphery to the spinal cord ventral horn have been reported in patients treated for spasticity [26].…”

“…Although differing in clinical manifestation, the fundamental mode of action -inhibition of neurotransmission -is common to all Clostridium neurotoxins [5,33,44]. In vitro and in vivo animal studies show that BTX alters acetylcholine, glutamate, noradrenaline, serotonin, dopamine, and glycine transmission, and may change the electrophysiologic properties, differentiation, and survival of central neurons [10]. Inhibition of neurotransmitter release by BTX is caused by the specific cleavage of a group of proteins integral to the exocytotic process, the SNARE proteins (soluble NSF-attachment protein receptors).…”