Botulinum Toxin Resistance (Tox Blox): It’s a real thing!

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…