Hello, I am Dr. Nicholas Godby, and I'm going to be talking to you today about chemodenervation with botulinum toxin. I do not have any relevant financial relationships to disclose. Today, we will be discussing the mechanism of action and the duration of botulinum toxins. We will describe toxin preparation and dilution. We will discuss the risks of injection with toxins and describe equipment needed for toxin preparation and injection. Upon injection of botulinum toxin, the toxin molecule binds to and is endocytosed by cell membranes. Once the toxin is intracellular, the toxin molecule cleaves snare proteins that are essential for vesicle fusion. Because vesicles are not able to fuse with cell membranes, their contents, acetylcholine in this case, cannot be released. This results in functional denervation with a subsequent decrease in muscle contraction. The effects on any given snare protein are permanent, but the neuromuscular junction will eventually regenerate such that the effects are clinically transient. Onset of action may be as early as two to five days, but is more often noted at around a week after injection. Maximum effects are typically noted at approximately two weeks out. The duration of action is somewhat variable patient-to-patient and toxin-to-toxin, with effects typically lasting 10 to 12 weeks, but sometimes longer. Anecdotally, I do have a few patients who only require injection every six months or so. There are eight botulinum toxin serotypes identified. These are all structurally similar, but are not all in widespread use. In the United States, there are three A-toxins and one B-toxin that are in clinical use. These are listed on the slide with trade names as well. The single B-toxin in common use comes in liquid form, but all A-toxins require reconstitution. This is performed by addition of preservative-free sterile saline added to the desired concentration of the injector. Again, the dilution is at the discretion of the injector, and there is no consensus on an appropriate concentration for injections. Most clinicians dilute to concentrations that facilitate dosing. Common preparations are listed above. Some physicians prepare more dilute concentrations for larger muscles to yield a higher volume of injectate. Personally, I reconstitute all incobotulinum and onobotulinum toxins to 10 units per 0.1 ml and use the above ratio for abobotulinum toxin listed. I use this concentration for all diagnoses, whether spasticity, dystonia, migraine, or any off-label uses. Toxin dosing is unique to each toxin. Both dosing ranges are recommended by the manufacturer. If converting from one toxin to another, the patient should be re-dosed. That is, the dose for each affected muscle should be recalculated based on the recommended dose ranges. There is no agreed-upon dose conversion to directly convert from one toxin to another. Although there are suggested dose conversions, these are not supported by any manufacturer or by the FDA. Speaking of dosing, this should also be individualized per patient, with the rule of thumb being to start low and go slow. You can always increase the toxin dose at a subsequent injection. There are risks to toxin injection. The risk most discussed is diffusion from the intended site, which can cause dysphagia, dry mouth, and weakness. I've personally seen this only once in my injecting career, and this was in a patient being injected with quite high doses, and they were being injected for dystonia rather than spasticity. More commonly, unintended consequences will be seen. There are times when a patient is using their tone in ways that are not apparent until it is treated and may develop unexpected loss of function. Fortunately, these unintended consequences should last no more than 10 to 12 weeks. Of course, also there is the possibility of development of neutralizing antibodies, particularly with injections given at increased frequency or frequency higher than recommended. There are relatively few contraindications to chemodenervation with toxin. These include allergy, pregnancy, infection or inflammation at the injection site, underlying neuromuscular junction disease, and concurrent aminoglycoside administration, as there is the theoretical risk that aminoglycosides exacerbate neuromuscular blockade. Equipment needed for injection is relatively minimal. Preservative-free sterile saline is needed for reconstitution, with needles and syringes for drawing up the medication. For injection, injectable electrodes can be used if EMG or stimulator guidance is utilized. If not, traditional needles and syringes can be guided with ultrasound. Which of the following statements is most correct regarding botulinum toxin's duration of action? A. Inactivation of SNARE proteins and clinical effects are permanent. B. Inactivation of SNARE proteins is permanent, but clinical effects are temporary. C. Inactivation of SNARE proteins is temporary, but clinical effects are permanent. Or D. Inactivation of SNARE proteins and clinical effects are temporary. The correct answer is B. While the inactivation of any given SNARE protein is permanent, regeneration of the neuromuscular junction will occur, such that clinical effects are temporary. In summary, botulinum toxin achieves chemodenervation by preventing acetylcholine release. While B toxins are prepared in liquid form, all A toxins require reconstitution with preservative-free sterile saline. This can be performed to the dilution preferred by the injector. There is no widely accepted dose conversion when transitioning from one toxin to another. And risks, benefits, and alternatives should always be discussed with your patient, but are generally low.

chemodenervation

botulinum toxin

dosing

contraindications

acetylcholine