Does Botox For Migraine Produce Disabling Neutralizing Antibodies?
Does Botox For Migraine Produce Disabling Neutralizing Antibodies?
Botox is a neurotoxic protein produced by the bacterium Clostridium botulinum which prevents the release of the neurotransmitter acetylcholine at the neuromuscular junction. This causes flaccid paralysis. Human infection with the bacterium causes the disease, botulism. However, the toxin is used commercially in medicine and cosmetics.
Botulism is a rare illness but is one of the most serious of all illnesses. Clostridium botulinum is an anaerobic, gram-positive, spore-forming rod commonly found on plants, in soil, water, and the intestinal tracts of animals. Humans ingest it through food like bulging, unopened canned foods which allow the bacteria to grow, or through contact with an open wound, or contaminated soil. Undiagnosed and untreated it may cause limb and breathing paralysis, sometimes resulting in death. Botulinum toxin is a potential biological weapon, so the U.S. military is interested in finding an anti-toxin or blocking molecule to protect soldiers.. The exact structure of the link between the toxin and nerve cell is now known, hopefully making it easier to find this blocking molecule. Just 1 gram of botulinum toxin could kill over 1 million people. Two kilograms could kill the entire human population of Earth.
Botulinum toxin acts at the neuromuscular junction to cause muscle paralysis by inhibiting the release of acetylcholine from presynaptic motor neurons. Botulinum toxins act at four different sites in the body: The neuromuscular junction, autonomic ganglia, postganglionic parasympathetic nerve endings and postganglionic sympathetic nerve endings that release acetylcholine. Botulinum toxin induces weakness of striated muscles by inhibiting transmission of alpha motor neurones at the neuromuscular junction. This has led to its use in conditions with muscular overactivity, such as dystonia. Transmission is also inhibited at gamma neurones in muscle spindles, which may alter reflex overactivity. The toxin also inhibits release of acetylcholine in all parasympathetic and cholinergic postganglionic sympathetic neurons. This has generated interest in its use as a treatment for overactive smooth muscles (for example, in achalasia) or abnormal activity of glands (for example, hyperhidrosis).
The toxin requires 24-72 hours to take effect, reflecting the time necessary to disrupt the nerve/muscleprocess. In very rare circumstances, some individuals may require as many as five days for the full effect to be observed. Peaking at about 10 days, the effect of botulinum toxin lasts nearly 8-12 weeks.
Botulinum toxin is the most acutely lethal toxin known. Botulinum toxin given subcutaneously via a small needle in small, safe amounts is useful for treating the following medical conditions.
For chronic migraine (15 headache days/month 8 of which have migraine features) Botox may be injected via a small needle in the muscles in the forehead, around the eyes, in the temples, and in the back of the head. It is administered every 3 months or 4 times a year. It is only approved for treating chronic migraine and should be discontinued if it is unsuccessful after the first 2 injections, or the first 6 months. Botox was not found to be effective for treatment of episodic migraine, which is less than 14 headache days per month.
Onabotulinumtoxin A (BoNT/A) is the product approved by the FDA for treating chronic migraine. Colloquially it is just called “Botox.”
Does Botox For Migraine Produce Disabling Neutralizing Antibodies? Yes, according to a recent report by Albrecht, et al, in Neurology January 01, 2019;92(1) entitled “High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy.” The migraine investigators found measureable antibodies (NAbs) which impair the effectiveness of Botox for chronic migraine. The investigators studied the prevalence of neutralizing antibodies (Nabs) against botulinum neurotoxin type A (BoNT/A) during long-term treatment of chronic migraine.
An estimated 5-15% of patients injected serially with earlier preparations of Botox® (79-11) developed secondary non-responsiveness from the production of neutralizing antibodies. Risk factors associated with the development of neutralizing antibodies include, injection of more than 200 units per session and repeat or booster injections given within one month of treatment. Hopefully, the new (BCB 2024) Botox® has reduced immunogenicity and a lower potential for neutralizing antibody production because of its decreased protein load, though the fact is not proven in clinical trial yet. In rabbit studies, no antibody formation occurred with new (BCB 2024) Botox® after six months of treatment, while old (79-11) Botox® caused antibody formation in all rabbits by five months.
Limited information is available on whether neutralizing antibodies resolve over time and, consequently, whether attempts at reinjection should be made after a prolonged period. An investigation is underway to determine whether injections of botulinum toxin type B are useful in patients with neutralizing antibodies to type A. Using the lowest dose of toxin necessary to achieve the desired clinical effect and avoiding reinjection within one month appear prudent in an effort to keep antibody formation as low and unlikely as possible.
How well does BoNT/A work for chronic migraine? Onabotulinumtoxin A (trade name Botox) received FDA approval for treatment of chronic migraine on October 15, 2010. The toxin is injected into the head and neck to treat chronic migraine. Approval followed evidence presented to the agency from two studies funded by Allergan showing a very slight improvement in incidence of chronic migraines for migraine sufferers undergoing the Botox treatment.
OnabotulinumtoxinA significantly reduced the number of headache days per 28-day cycle relative to placebo at week 24 (change from baseline: -8.4 days for onabotulinumtoxinA versus -6.6 days for placebo; P < 0.001, pooled data). OnabotulinumtoxinA improved health-related quality of life and had an acceptable safety profile.
What did the investigators find? Albrecht, et al, found that 83 of 596 patients (13.9 %) had measurable NAbs. It was found that the probability of developing NAbs increased with single and cumulative dose of treatment.and treatment duration had no additional influence. Albrecht, et al, stated, “Repeated injections of BoNT/A inevitably bear the risk of developing NAbs.” The dose per injection session should be kept as low as possible to avoid development of NAbs.
What does it mean for chronic migraine treatment that patients develop antibodies from Botox? The development of antibodies means that Botox will no longer be as effective for treatment. Without antibody development Botox reduced chronic migraine headaches only 1.8 days more than placebo.
Good luck with this.
Britt Talley Daniel MD