Explanation of timing of botulinum neurotoxin effects, onset and duration, and clinical ways of influencing them

•After botulinum toxin is injected, it is taken up into nerve terminals, so injection into endplate zones is optimal.•Botulinum toxin uptake is activity dependent.•Injection of botulinum toxin into muscle distributes the toxin mainly by convection.•Toxin not taken up into the nerve terminals is washed out of the muscle into the general circulation.•Toxin is active in the presynaptic terminal until metabolized.

While the steps in the action of botulinum neurotoxin (BoNT) are well known, the factors underlying the timing of these steps are not fully understood. After toxin is injected into a muscle, it resides in the extracellular space and must be taken up into the nerve terminals. More toxin will be taken up if near the endplate. Toxin is distributed mainly by convection and there is likely little diffusion. Toxin that is not taken up will go into the general circulation where it may have a slight systemic effect. The uptake is activity and temperature dependent. Encouraging the unwanted muscle contractions after injection should be helpful. Cooling will decrease the uptake. The times for washout from the extracellular space and uptake of the toxin are not well established, but are likely measured in minutes. Toxin in the general circulation has a long half time. The time from injection to weakness is determined by how long it takes to get sufficient damage of the SNARE proteins to interfere with synaptic release. Toxins are zinc dependent proteases, and supplemental zinc may produce a greater effect. There will be weakness as long as there is residual toxin in the nerve ending.