ABSTRACT
Thus, factors influencing BTX diffusion are important to know. In theory, as noted by Dr Aoki, botulinum neurotoxin protein complexes of greater molecular weight (i.e. BOTOX) should diffuse more slowly than those of lower molecular weight (i.e. Dysport and NeuroBloc). However, this theoretical assumption conflicts with two lines of argument. First, it is questionable whether this basic physiological rule can be simply applied to the diffusion of BTX in the human body. Indeed, after injection in a muscle, BTX does not diffuse in a homogeneous milieu. Its spread is influenced by anatomical factors such as the architecture of the injected muscles4 and the presence of muscle fasciae, which reduces the spread of toxin by approximately 23%.5 Second, the clinical studies available do not support the hypothesis of a difference in diffusion pattern for BOTOX and Dysport. The two studies which appropriately addressed this issue are prospective controlled studies specifically comparing the incidence of local adverse events occurring with BOTOX and Dysport in a given pathology (i.e. cervical dystonia),2,6 with a methodology avoiding confounding factors such as volume of the injectate and dilution. Other studies did not directly compare the two products, and/or had basic methodological flaws that prevented any conclusion to be drawn. In the first study,6 the authors failed to reveal any difference between the two products at a 1:3 ratio. In our study,2
we found a greater efficacy of Dysport versus BOTOX at the same ratio, associated with a slight increase in dysphagia incidence in the Dysport group. Our interpretation is that the increased rate of swallowing difficulties is due to the relative overdosage of Dysport compared to BOTOX at this 1:3 ratio. Nothing allows further use of this observation as an argument for a different spreading pattern of the two products. Apart from the above described anatomical factors,
which are, by definition, non-modifiable, the spreading pattern of BTX may also vary according to factors that can be modified by the clinician: dose, volume, and technique of injection. It has been shown that the higher are the doses and the volume, the greater is the diffusion.7,8 The number of injection points may also play a role. Several injection points distributed in the target muscle can insure that the highest possible number of neuromuscular junctions are reached, but this carries a higher risk of diffusion to adjacent muscles. In addition, the direction of the needle may have
some importance when the target muscle is located in the vicinity of a functionally important muscle. For example, to inject the orbicularis oculi, it is preferable to direct the tip of the needle outwards, in order to avoid spread towards the levator palpebrae, and subsequent undesirable ptosis. Thus, clinicians can adapt the procedure to the clini-
cal situation. When careful selectivity is warranted (for example in cosmetic indications), it can be interesting to use a low dilution (high concentration), and/or a single injection point, and/or a lower dose. Conversely, injecting large muscles (in spasticity, for example) most often requires a higher dilution (low concentration), and/or multiple injection sites, and/or higher doses. In cosmetic uses, certain practitioners recommend using in the same session a higher volume for larger muscles such as the frontalis, and smaller volumes to treat functionally sensitive areas such as the eyelids or the mouth.8,9
Remote adverse effects are much rarer than local ones, but are potentially severe, ranging from asthenia to generalized weakness and life-threatening botulismlike syndrome. Dysphagia is considered a remote effect when the injected muscles are distant from the pharyngeal musculature, but a local side-effect when it occurs after injection of the cervical muscles. In case of doubt, distant spread of the toxin can be proved by electromyography showing increased jitter and blockings in distant muscles.10,11
The remote effects of BTX are not completely understood, but are supposed to be due to a hematogenous spread of the toxin. Retrograde axonal spread of toxin could be another explanation, but has never been proved in humans. No study has examined the responsible factors, but
analysis of the published cases reveals that most occurred after detrusor injections12-14 or spasticity,15,16
and/or after the use of high dilutions,12 and/or in patients with underlying motor deficit. In most patients the three risk factors were present, and we can hypothesize that the conjunction of two or more risk factors may be responsible for the occurrence of such effects. Detrusor injection is probably an at-risk procedure in itself, because the bladder wall, especially between trabeculation bars, is thin, and can allow diffusion perivesically. In that particular case, but also when high doses are needed such as in spasticity, it is advisable to avoid high dilutions. Finally, distant adverse events have been reported more frequently with Dysport12,13,15-18 than with BOTOX,12,14 but no definite conclusion can be drawn from simple case reports. The only way to address this issue would be to perform a large, independent, prospective, controlled study to establish the mechanism and risk factors (including toxin formulation) of the distant spread of the toxin.
