Botulinum toxin is a medication and a neurotoxic protein produced by the bacterium Clostridium botulinum, and is known to be very toxic with an LD50 of roughly 0.005�0.05 �g/kg making it the most toxic substance known to man. Despite its deadly toxic effect, it is sometimes used in very small doses to treat muscle spasms. Popularly known by one of its trade names, Botox, botulinum toxin is now commonly used in various settings for cosmetic procedures.
Justinus Kerner described botulinum toxin as a “sausage poison” and “fatty poison”, as this bacterium often caused poisoning by growing in improperly handled or prepared meat products. It was Kerner, a physician, who first conceived a possible therapeutic use of botulinum toxin and coined the name botulism. (In Latin, botulus means “sausage.”) In 1897, Emile van Ermengem identified the bacterium Clostridium botulinum to be the producer of botulinum toxin. In 1928, P. Tessmer Snipe and Hermann Sommer for the first time purified the toxin. In 1949, Burgen’s group discovered that botulinum toxin blocks neuromuscular transmission.
In the late 1960s Alan Scott, M.D., a San Francisco ophthalmologist, and Edward Schantz were the first to work on a standardized botulinum toxin preparation for therapeutic purposes. By 1973, Scott (now at Smith-Kettlewell Institute) used botulinum toxin type A (BTX-A) in monkey experiments, and, in 1980, he officially used BTX-A for the first time in humans to treat strabismus “crossed eyes”, a condition in which the eyes are not properly aligned with each other, and “uncontrollable blinking” (blepharospasm).
Blepharospasm and strabismus
The possibility of using botulinum toxin as a therapeutic agent was investigated in the early 1980’s by groups of university-based ophthalmologists scattered throughout the U.S.A. and Canada. By 1985 a scientific protocol of injection sites and dosage had been empirically determined for treatment of blepharospasm and strabismus. Side effects had been evaluated and were deemed to be rare, mild and treatable. The beneficial effects of the injection lasted only 4�6 months, so that blepharospasm patients had to return to the clinics for re-injection two or three times a year.
In 1986 Scott’s micro-manufacturer and distributor of BOTOX was no longer able to supply the drug because of an inability to obtain product liability insurance. Patients became desperate as supplies of BOTOX were gradually consumed, forcing him to abandon patients who would have been due for their next injection. For a period of four months American blepharospasm patients had to arrange to have their injections performed by participating doctors at Canadian eye centers until the liability issues could be resolved.
In December 1989, BOTOX manufactured by Allergan, Inc., was approved by the U.S. Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old.
The cosmetic effect of BTX-A on wrinkles was originally documented by a plastic surgeon from Sacramento, California, Dr. Richard Clark, and published in Plastic and Reconstructive Surgery in 1989. Similar effects had reportedly been observed by a number of independent groups (Brin, and the Columbia University group). On April 15, 2002, the FDA announced the approval of botulinum toxin type A (BOTOX Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines). Cosmetic use of botulinum toxin type A has become widespread with many celebrities, such as Kim Kardashian, viewing it as less intrusive and/or artificial than other types of plastic surgery.
The acceptance of BTX-A use for the treatment of muscle pain disorders is growing, with approvals pending in many European countries and studies on headaches (including migraine), pro static symptoms, asthma, obesity and many other possible indications are ongoing.
Upper Motor Neuron Syndrome
BTX-A has become a frequently used treatment for muscles affected by the Upper Motor Neuron Syndrome, for muscles with an impaired ability to effectively lengthen. Muscles affected by the Upper Motor Neuron Syndrome frequently are limited by weakness, loss of reciprocal innervation, decreased movement control and spasticity. Joint motion may be restricted by severe muscle imbalance related to the Upper Motor Neuron Syndrome, when some muscles are markedly overactive. Injecting an overactive muscle to decrease its level of contraction can allow improved reciprocal motion, and so improved ability to exercise. In June 2009 its use for treating muscles with spasticity led a UK doctor to successfully help an Australian man who had required a wheelchair for mobility following a stroke 20 years prior to walk.
Bushara and Park were the first to show that botulinum toxin injections inhibit sweating while treating patients with hemifacial spasm at Southend Hospital in England in 1993. They further showed the efficacy of botulinum toxin in treating hyperhidrosis (excessive sweating). BTX-A was later approved for the treatment of excessive underarm sweating.
Botulinum Toxin Type B (BTX-B) received FDA approval for treatment of cervical dystonia on December 21, 2000. Trade names for BTX-B are Myobloc in the United States, and Neurobloc in the European Union.
In the United States, BOTOX is manufactured by Allergan, Inc. for both therapeutic and cosmetic use.
Dysport, a therapeutic formulation of the type A toxin developed and manufactured in Ireland, is licensed for the treatment of focal dystonias and certain cosmetic uses in many territories worldwide.
Lanzhou Institute (China) manufactures a BTX-A product, producing 50U and 100U type A toxin.
Neuronox, a BTX-A product, was introduced by Medy-Tox Inc. of South Korea, in 2009.
The original version of BOTOX was delivered in vial for injection with a syringe.
A technique dubbed Microdroplet� Botox� was invented with the claim that it injects Botox more precisely and with more predictable results. Other physicians debate whether the technique is anything more than using smaller needles and whether it merits a trademarked name.
Botulinum toxin is denatured at temperatures greater than 60�C (140�F).
Botulism toxins is produced by these bacteria: Clostridium botulinum, C. butyricum, C. baratii and C. argentinense.
Chemical overview and lethality
There are seven serologically distinct toxin types, designated A through G. Additionally, six of the seven toxin types have subtypes with five subtypes of BoNT A having been described. The toxin is a two-chain polypeptide with a 100-kDa heavy chain joined by a disulphide bond to a 50-kDa light chain. This light chain is an enzyme (a protease) that attacks one of the fusion proteins (SNAP-25, syntaxin or synaptobrevin) at a neuromuscular junction, preventing vesicles from anchoring to the membrane to release acetylcholine. By inhibiting acetylcholine release, the toxin interferes with nerve impulses and causes flaccid (sagging) paralysis of muscles in botulism, as opposed to the spastic paralysis seen in tetanus.
It is the most acutely toxic substance known, with a median lethal dose of about 1 ng/kg when introduced intravenously and 3 ng/kg when inhaled This means that, depending on the method of introduction into the body, a mere 90�270 nanograms of botulinum toxin could be enough to kill an average 90 kg (200 lb) person.
Food-borne botulism usually results from ingestion of food that has become contaminated with spores (such as a perforated can) in an anaerobic environment, allowing the spores to germinate and grow. The growing (vegetative) bacteria produce toxin. It is the ingestion of preformed toxin that causes botulism, not the ingestion of the spores or the vegetative bacteria. Infant and wound botulism both result from infection with spores, which subsequently germinate, resulting in production of toxin and the symptoms of botulism.
Proper refrigeration at temperatures below 3�C (38�F) prevents the growth of Clostridium botulinum. The organism is also susceptible to high salt and low pH levels. The toxin itself is rapidly destroyed by heat, such as in thorough cooking. On the other hand, the spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time. Fortunately, ingestion of the spores is safe, except in infants, as the highly oxygenated and highly acidic environment of an adult human digestive system prevents the spores from growing and producing the botulinum toxin.
Botulinum toxin has been recognized and feared as a potential bioterror weapon. Intentional exposure to the toxin in a bioterrorism attack would most likely occur by poisoned food or water, or through breathing in the toxin.
Although botulinum toxin is a lethal naturally occurring substance, it can be used as an effective and powerful medication. Researchers discovered in the 1950s that injecting overactive muscles with minute quantities of botulinum toxin type-A would result in decreased muscle activity by blocking the release of acetylcholine from the neuron by preventing the vesicle where the Acetylcholine is stored from binding to the membrane where the neurotransmitter can be released. This will effectively weaken the muscle for a period of three to four months.
In cosmetics, a Botox injection, consisting of a small dose of botulinum toxin, can be used to prevent formation of wrinkles by paralyzing facial muscles. As of 2007, it is the most common cosmetic operation, with 4.6 million procedures in the United States, according to the American Society of Plastic Surgeons. Qualifications for Botox injectors vary by county, state and country. Botox Cosmetic providers include dermatologists, plastic surgeons, cosmetic physicians, nurses practitioners, nurses, physician assistants, and medical spas. The wrinkle preventing effect of Botox lasts for approximately three to four months, up to six months.
In addition to its cosmetic applications, Botox is currently used in the treatment e.g. spasms and dystonias, by weakening involved muscles, for the 60-70 day effective period of the drug. The main conditions are:
•Cervical dystonia (spasmodic torticollis) (a neuromuscular disorder involving the head and neck)
•Blepharospasm (excessive blinking)
•Severe primary axillary hyperhidrosis (excessive sweating)
•Achalasia (failure of the lower oesophageal sphincter to relax)
•Local intradermal injection of BTX-A is helpful in chronic focal painful neuropathies. The analgesic effects are not dependent on changes in muscle tone.
•Migraine and other headache disorders, although the evidence is conflicting in this indication
Other uses of botulinum toxin type A that are widely known but not specifically approved by FDA (off-label uses) include treatment of:
•Pediatric incontinence, incontinence due to overactive bladder, and incontinence due to neurogenic bladder.
•Anal fissure•Spastic disorders associated with injury or disease of the central nervous system including trauma, stroke, multiple sclerosis, Parkinson’s disease, or cerebral palsy
•Focal dystonias affecting the limbs, face, jaw, or vocal cords
•TMJ pain disorders
•Vocal cord dysfunction (VCD) including spasmodic dysphonia and tremor
•Reduction of the Masseter muscle for decreasing the size of the lower jawTreatment and prevention of chronic headache and chronic musculoskeletal pain are emerging uses for botulinum toxin type A. In addition, there is evidence that Botox may aid in weight loss by increasing the gastric emptying time.
Links to deaths
In September 2005, a paper published in the Journal of American Academy of Dermatology reported from the FDA saying that use of Botox has resulted in 28 deaths between 1989 and 2003, though none were attributed to cosmetic use.
On February 8, 2008, the FDA announced that Botox has “been linked in some cases to adverse reactions, including respiratory failure and death, following treatment of a variety of conditions using a wide range of doses,” due to its ability to spread to areas distant to the site of the injection.
In January 2009, the Canadian government warned that botox can have the adverse effect of spreading to other parts of the body, which could cause muscle weakness, swallowing difficulties, pneumonia, speech disorders and breathing problems.
Several cases of death have been linked to the use of fake Botox, one of the causes of death listed on the Spike TV show, “1000 Ways to Die”.
Side effects, which are generally minor and temporary, can be predicted from the mode of action (muscle paralysis) and chemical structure (protein) of the molecule, resulting broadly speaking in two major areas of side effects: paralysis of the wrong muscle group and allergic reaction. Bruising at the site of injection is a side effect not of the toxin, but rather the mode of administration. In cosmetic use, this can result in inappropriate facial expression such as drooping eyelid, double vision, uneven smile, or loss of the ability to close eyes. This will wear off in around six weeks. Bruising is prevented by the clinician applying pressure to the injection site, but may still occur, and will last around 7�10 days. When injecting the masseter muscle of the jaw, loss of muscle function will result in a loss or reduction of power to chew solid foods. All cosmetic treatments are of limited duration, and can be as short a period as six weeks, but usually one sees an effective period of between three and eight months. At the extremely low doses used medicinally, botulinum toxin has a very low degree of toxicity.
Other adverse events from cosmetic use include headaches, dysphagia, flu-like syndromes, and allergic reactions.
There has been a petition by Public Citizen to the FDA requesting regulatory action concerning the possible spread of botulinum toxin (Botox, Myobloc) from the site of injection to other parts of the body (HRG Publication #1834): Public Citizen
Individuals who are pregnant, have egg allergies or a neuromuscular disorder are advised to avoid Botox.