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By: Dr. Amy Miller
Have you been getting tox treatments (Botox, Dysport, Xeomin, or Jeuveau) for wrinkles and noticed that it does not seem to be working as well as it did in the beginning? Maybe it’s not lasting as long or maybe it just doesn’t seem as strong as is did originally? No, you are not crazy and no, your injector probably isn’t doing anything different or nefarious. You may be one of a small but growing number of patients who can/will develop immune mediated resistance to neurotoxin injections. It really is a bummer. In essence, your body is treating the neurotoxin like a vaccine-it is creating antibodies to neutralize the effect of the toxin, in an effort to protect you. The good news? If this was the 1300’s you are protected against botulinum poising, yay! Congrats! Your award for surviving botulinum poisoning is RBF because now your Botox is not going to work.
Think of it this way, when you get a measles vaccine, for example, it stimulates your white blood cells to make a weapon specifically for that illness, so next time the measles virus tries to invade the weapons are ready, deployed without delay and the measles virus is killed. If you get exposed to measles in the future you most likely will not even be aware of the mini war going on inside you, and since you never get sick with the measles you don’t appreciate the close call you just had! So, this system is pretty amazing is general and helps keep us safe from all those killer diseases of the past. Anyone remember the iron lung for polio victims? Our amazing white blood cells help protect us from that when we get the polio vaccine.
For some reason, some of us have eager, extra hardworking WBCs that create antibodies (think smart bomb or weapon) against the neurotoxin (which was originally injected to relax the muscles that cause frown lines, crows feet, RBF etc). These antibodies incapacitate the toxin, and the muscles are unaffected, continuing to contract away to create and deepen wrinkles. The rocket scientists that study this type of thing (immunologists) like to divide patients who do not respond to tox injections and have Tox Blox into 2 categories: primary non responders (PNR) and secondary non responders (SNR).
PNR refers to a situation in which patients in whom botulinum toxin injections fail to improve symptoms from the very first injection and all subsequent treatments (1). This is rare in clinic populations (2) but can occur in military personnel who were vaccinated against botulism. SNR occurs when patients derive benefit from at least one injection cycle but lose that benefit over subsequent injection cycles (3). This SNR or Tox Blox seems to be occurring more in the cosmetic and therapeutic toxin treatment patient population and no one is sure why.
It could be that since more people in general, are getting tox treatments more people therefore are finding they are non-responders and have Tox Blox. The real question is whether repeated injections over time create or cause Tox Blox. Most experts think both play a role in the increasing amount of tox resistance.
Of course, it is important to try and determine if antibodies are truly the cause of Tox Blox. Sometimes muscles hypertrophy (get stronger) with age and maybe the doses of tox that worked in the beginning are too weak over time. The toxins are very fragile until they get in the body and are susceptible to breakdown because of temperature and acidity changes during shipping and storage. They can be denatured by aggressive mixing or shaking when reconstituted with saline prior to injection. Another factor contributing to the impression of non-response is the trend towards use of lower doses for a more ‘natural” look. If you are used to your eyebrows not furrowing at all but your new injector wants to preserve some movement for a natural appearance, he or she may use a lower dose. It then may appear that the tox is no longer working or not working as well. This may seem like Tox Blox but in reality is just a communication issue between you and your injector, resulting in a sub therapeutic dose.
When antibody formation is the true cause of Tox Blox it can be difficult to impossible to definitively diagnose. There are blood tests that can be performed to check for tox resistance, but they are pretty lousy. Approximately half of patients determined to have SNR, when tested, had NO antibodies (4), and several responders were found to have neutralizing antibodies. This probably means that we simply don’t have the right test or sensitive enough tests. This just adds to the confusion surrounding true immune-mediated tox resistance.
Another factor to contemplate are “NAPS” or neurotoxin associated proteins that come with the active toxin. Some brands of tox contain these and some do not. The NAPS function, in nature, to protect the sensitive toxin from environmental factors that may cause it to breakdown. These proteins are quite immunogenic, meaning they rev up the white blood cells to produce antibodies. Xeomin, which has been purified to have no NAPS is often referred to as the “naked” Botox. In a paper published last year, Xeomin was found to have 0% of patients with neutralizing antibodies. Botox was the next best as 0.6% of pts producing antibodies and dysport the worse at 5.3% (5). Jeuveau and Daxxify were not tested. Daxxify is the newest tox on the market, it also lacks the NAPS except for one small protein that helps it last longer and confers a longer duration of action. If you have been using botox, dysport or Jeuveau, all which retain the NAPs in their formulation, and have developed Tox Blox, it may be worth trying Xeomin or Daxify. Additionally, it may be best for all newbies to start with Xeomin to try to prevent future antibody induced tox resistance.
There is a Hail Mary out there for those of you who are truly resistant to the core botulinum toxin and have true Tox Blox. It is called Myobloc and it is a different subtype of the toxin that is not approved for cosmetic use. It is FDA approved to use for a condition called cervical dystonia, so it is available in the states. It can be used “off label” if both the physician and patient agree any risks are worth the benefit of its use. The downside is that it has lots of those associated proteins, NAPS, and most patients develop immunity to it as well. In fact, 86% will develop nonresponse after 5 applications (6). A “naked” Myobloc would be interesting to test, if it can be manufactured without the NAPs. Alas, it does not exist, yet…
Tox Blox, or botulinum toxin antibody-induced resistance, is something that will be getting more attention as more patients are found to have it. If you have questions about Tox Blox, or treatment for Tox Blox, reach out to us here at St. Louis Skin Solutions. You are not the only one! Our lead medical assistant, Gwen, who no longer responded to any of the toxins is now finally responding to Myobloc. She can tell you all about her experience with Tox Blox. Mention this blog and get $25 of your Xeomin, Daxxify or Myobloc treatment!
- Dressler D. Clinical presentation and management of antibody-induced failure of botulinum toxin therapy. Mov Disord. 2004 Mar;19 Suppl 8:S92-S100. doi: 10.1002/mds.20022. PMID: 15027060.
- Ramirez-Castaneda J, Jankovic J. Long-term efficacy and safety of botulinum toxin injections in dystonia. Toxins (Basel). 2013 Feb 4;5(2):249-66. doi: 10.3390/toxins5020249. PMID: 23381141; PMCID: PMC3640534.
- Bellows, S., & Jankovic, J. (2019). Immunogenicity Associated with Botulinum Toxin Treatment. Toxins, 11(9), 491. https://doi.org/10.3390/toxins11090491
- Fabbri M, Leodori G, Fernandes RM, Bhidayasiri R, Marti MJ, Colosimo C, Ferreira JJ. Neutralizing Antibody and Botulinum Toxin Therapy: A Systematic Review and Meta-analysis. Neurotox Res. 2016 Jan;29(1):105-17. doi: 10.1007/s12640-015-9565-5. PMID: 26467676.
- Ho WWS, Albrecht P, Calderon PE, Corduff N, Loh D, Martin MU, Park JY, Suseno LS, Tseng FW, Vachiramon V, Wanitphakdeedecha R, Won CH, Yu JNT, Dingley M. Emerging Trends in Botulinum Neurotoxin A Resistance: An International Multidisciplinary Review and Consensus. Plast Reconstr Surg Glob Open. 2022 Jun 20;10(6):e4407. doi: 10.1097/GOX.0000000000004407. PMID: 35747253; PMCID: PMC9208887.
- Dressler D, Eleopra R. Clinical use of non-A botulinum toxins: botulinum toxin type B. Neurotox Res. 2006 Apr;9(2-3):121-5. doi: 10.1007/BF03033929. PMID: 16785108.