Researchers studying whether botulinum neurotoxin (BoNT) A, BoNT/D and tetanus toxin (TeNT) can spread within networks of neurons to have distal effects found that indeed they do.
Specifically, they found that while the toxins act on the targeted neurons, they are also taken up, via an alternative pathway, where they are transported and released to exert effects on upstream neurons.
The result, at least in a lab dish, is long-distance effects, according to the study, epublished August 4 in Cell Reports.
According to a university press release on the study, the concern isn’t new. In 2009, the FDA added a warning in prescribing information, noting that botulinum toxin may spread from the area of injection to produce symptoms consistent with botulism, such as unexpected loss of strength or muscle weakness, swallowing and breathing difficulties that can be life-threatening.
There are also those “puzzling” results from Botox and other treatments, according to study author Ewa Bomba-Warczak, a doctoral candidate in neuroscience.
“In many cases, after an injection for a disabling spasm of neck muscles called cervical dystonia, there is no change in muscle tone but the patient finds relief and is perfectly happy. That result can’t be explained by the local effects,” Bomba-Warczak says in the release.
Dr. ChapmanIn the study, the researchers used mouse neurons in wells connected by tiny channels that allow growth of axons.
“Every time one fraction of the toxin acts locally (on the first nerve cell it contacts), another fraction acts at a distance,” says study author Edwin Chapman, Ph.D., investigator, Howard Hughes Medical Institute, and professor of neuroscience at the University of Wisconsin-Madison. “It’s unknown how far they travel, which likely depends on the dose of toxin and other factors.”
Implications for the Cosmetic Practice
Dr. FanSan Francisco-based plastic surgeon Larry Fan, M.D., says the study has no new implications for cosmetic practice.
“It is well known that botulinum toxin can spread from an injection site via passive diffusion, intraneuronal transfer or through the bloodstream. This study provides direct evidence that botulinum neurotoxin can spread distally between nerve cells,” Dr. Fan says. “Botox injection for cosmetic use remains a safe treatment. However, all patients should keep in mind that there is a small possibility of undesired effects such as temporary eyelid or eyebrow drooping.”
The study’s findings underscore the importance of the injector’s qualifications.
“A qualified injector should possess extensive knowledge of facial anatomy, aging, injection technique, botulinum pharmacology and treatment of potential complications,” Dr. Fan says. “The only injectors who consistently possess these skills and knowledge, with a few exceptions, include board-certified plastic surgeons, facial plastic surgeons and dermatologic surgeons.”
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Lessons to Be Learned
Miami, Fla. cosmetic surgeon John J. Martin Jr., M.D., agrees that clinically there can be spread or diffusion of the injectable fluid beyond the area of injection, but there are lessons to be learned from the study.
“… this study shows that it may also spread from cell to cell. This confirms that physicians have to be careful when injecting into areas where you don't want any spread, such as the upper eyelid,” Dr. Martin says.
Dr. Martin says that while the study release implies distant spread to remote areas, the findings confirm spread into adjacent, not remote or distant locations.
“There have been instances of remote spread from high-dose injections. In these cases there is so much toxin being injected that there is systemic spread leading to symptoms of botulism. This is not seen with normal cosmetic doses, which all doctors should abide by,” Dr. Martin says.
Dr. FreimanMiami, Fla., plastic surgeon Jacob Freiman, M.D., has his doubts about the implications of findings like these for cosmetic practice.
“I believe this topic is being sensationalized based on a vague study that shows that the botulism toxin can propagate from one neuron to the adjacent one. So far, there has been very little bench research … and no real trials,” Dr. Freiman says. “If you look broadly at the millions of people who have gotten and will get Botox injections, you would be hard pressed to find someone who has any distant effects. At most, over-injection in one area can cause more than the just the specific target muscle to be paralyzed and the tiny muscle right next to it may also be paralyzed. This can sometimes be seen with patients who go for Botox and have a droopy upper eyelid. Eye drops can generally help resolve the issue.”
NEXT: Botox 2.0?
Botox 2.0?
Dr. ChabokiHoutan Chaboki, M.D., a facial plastic surgeon in Washington, DC, says he finds the study interesting.
“The doses for cosmetic uses are generally much smaller than other medical uses for botulinum toxin,” Dr. Chaboki says. “Anecdotal evidence among plastic surgeons hasn't shown a clinical effect of this possible neuron-to-neuron transfer of the toxin beyond the injection site. Injecting muscle for forehead wrinkles hasn't affected smiling muscles, for example. It does, however, encourage drug manufacturers to develop a newer, modified version of botulinum toxin that doesn't travel. Botox 2.0.”
Dr. WienerChicago plastic surgeon Gregory Wiener, M.D., says he thinks the study is informative and welcomes any increase in the safety profile of the products he uses.
“However, after 17 years of using Botox for cosmetic applications, I can say that clinically we just don’t see the effect spreading to adjacent (much less distant) areas,” Dr. Wiener says. “As long as the Botox dose is appropriate, the fluid used to reconstitute and deliver the Botox kept to a minimum and the injection techniques are low pressure and focused, it is extremely rare to see unwanted effects in surrounding areas,” Dr. Wiener says.
NEXT: Avoiding Unwanted Effects
Avoiding Unwanted Effects
Dr. Martin says that to avoid spread cosmetic surgeons should not use a highly-diluted preparation of the toxin or a high-dosage and only inject into areas that they want to paralyze.
“Some local diffusion is expected, so they should be careful when injecting into certain areas that are known to be sensitive (such as around the upper lid to elevate the brow) and air on the side of being conservative with dosages,” he says. “You can always add more once the solution has settled, but the same can’t be said the other way around.”
Dr. Wiener tailors injection techniques and Botox doses to each patient, but considers such things as strength of the muscular contraction and thickness of the skin and tissues.
“If these types of guidelines are not followed, there may be a higher incidence of unwanted effects (as in personnel with less training and experience),” Dr. Wiener says. “And in some cases, when larger doses and higher numbers of injections are done, such as treating hyperhidrosis (excessive sweating), there is more potential for unwanted effects. In these instances, a more focused Botox would be appropriate."
In some types of injections, like the forehead and crow’s feet, injectors actually want a small amount of diffusion and spreading of the effects in order to block these large, flat muscles over a wider area, Dr. Wiener says.
“A Botox with more focused effect in this situation may take additional injections for adequate treatment," Dr. Wiener says.
Dr. MoellekenIt’s important that the injector be familiar with not only the anatomy, but also the volume of distribution of the various botulinum preparations. The injector needs to perform an appropriate history and physical prior to treatment. He or she needs to know how to treat complications should they occur, according to Brent Moelleken, M.D., Beverly Hills plastic surgeon and associate clinical professor of plastic surgery at UCLA.
“A medi-spa is not the place to have a complication from errant botulinum toxin injection,” Dr. Moelleken says.
Dr. Moelleken says he injects botulinum toxin only in an office setting for that reason and disagrees with the commoditization of botulinum toxin with advertisements on billboards and buses.
“While in the proper hands botulinum toxin is quite safe, complications can and do occur, up to and including death," Dr. Moelleken says.
