Initial descriptions and discovery One of the earliest recorded outbreaks of foodborne botulism occurred in 1793 in the village of
Wildbad in what is now
Baden-Württemberg, Germany. Thirteen people became sick and six died after eating pork stomach filled with
blood sausage, a local delicacy. Additional cases of fatal food poisoning in
Württemberg led the authorities to issue a public warning against consuming smoked blood sausages in 1802 and to collect case reports of "sausage poisoning". Between 1817 and 1822, the German physician
Justinus Kerner published the first complete description of the symptoms of botulism, based on extensive clinical observations and animal experiments. He concluded that the toxin develops in bad sausages under anaerobic conditions, is a biological substance, acts on the nervous system, and is lethal even in small amounts. In 1870, the German physician Müller coined the term
botulism to describe the disease caused by sausage poisoning, from the Latin word , meaning 'sausage'. On 14 December 1895, there was a large outbreak of botulism in the Belgian village of
Ellezelles that occurred at a funeral where people ate pickled and smoked ham; three of them died. By examining the contaminated ham and performing autopsies on the people who died after eating it, van Ermengem isolated an anaerobic microorganism that he called
Bacillus botulinus. As a result of Kerner's and van Ermengem's research, it was thought that only contaminated meat or fish could cause botulism. This idea was refuted in 1904 when a botulism outbreak occurred in
Darmstadt, Germany, because of canned white beans. In 1910, the German microbiologist J. Leuchs published a paper showing that different strains of
Bacillus botulinus caused the outbreaks in Ellezelles and Darmstad and that the toxins were serologically distinct.
World War II With the outbreak of World War II, weaponization of botulinum toxin was investigated at
Fort Detrick in Maryland. Carl Lamanna and James Duff developed the concentration and crystallization techniques that Edward J. Schantz used to create the first clinical product. When the Army's
Chemical Corps was disbanded, Schantz moved to the Food Research Institute in Wisconsin, where he manufactured toxin for experimental use and provided it to the academic community. The mechanism of botulinum toxin action – blocking the release of the neurotransmitter acetylcholine from nerve endings – was elucidated in the mid-20th century, and remains an important research topic. Nearly all toxin treatments are based on this effect in various body tissues.
Cold War The
Soviet biological weapons program began a program focusing on botulinum toxin from 1951 at the Ministry of Defence's Scientific-Research Institute of Hygiene in
Sverdlovsk Oblast. The
United States biological weapons program possessed botulinum toxin before it was
disbanded in 1969. The
Iraqi biological weapons program began developing botulinum toxin at its
Al Hakum production plant from 1989, the basis for which it originally received among a range of agents from the
American Type Culture Collection in 1988.
Strabismus Ophthalmologists specializing in eye muscle disorders (
strabismus) had developed the method of EMG-guided injection (using the
electromyogram, the electrical signal from an activated muscle, to guide injection) of local anesthetics as a diagnostic technique for evaluating an individual muscle's contribution to an eye movement. Because
strabismus surgery frequently needed repeating, a search was undertaken for non-surgical, injection treatments using various anesthetics, alcohols, enzymes, enzyme blockers, and snake neurotoxins. Finally, inspired by
Daniel B. Drachman's work with chicks at Johns Hopkins,
Alan B. Scott and colleagues injected botulinum toxin into monkey extraocular muscles. The result was remarkable; a few picograms induced paralysis that was confined to the target muscle, long in duration, and without side effects. After working out techniques for freeze-drying, buffering with
albumin, and assuring sterility, potency, and safety, Scott applied to the FDA for investigational drug use, and began manufacturing botulinum type A neurotoxin in his San Francisco lab. He injected the first strabismus patients in 1977, reported its clinical utility in 1980, and had soon trained hundreds of ophthalmologists in EMG-guided injection of the drug he named Oculinum ("eye aligner"). In 1986, Oculinum Inc, Scott's micromanufacturer and distributor of botulinum toxin, was unable to obtain product liability insurance, and could no longer supply the drug. As supplies became exhausted, people who had come to rely on periodic injections became desperate. For four months, as liability issues were resolved, American blepharospasm patients traveled to Canadian eye centers for their injections. Allergan then began using the trademark Botox.
Cosmetics The effect of botulinum toxin type-A on reducing and eliminating forehead wrinkles was first described and published by Richard Clark, MD, a plastic surgeon from Sacramento, California. In 1987 Clark was challenged with eliminating the disfigurement caused by only the right side of the forehead muscles functioning after the left side of the forehead was paralyzed during a facelift procedure. This patient had desired to look better from her facelift, but was experiencing bizarre unilateral right forehead eyebrow elevation while the left eyebrow drooped, and she constantly demonstrated deep expressive right forehead wrinkles while the left side was perfectly smooth due to the paralysis. Clark was aware that botulinum toxin was safely being used to treat babies with strabismus and he requested and was granted FDA approval to experiment with botulinum toxin to paralyze the moving and wrinkling normal functioning right forehead muscles to make both sides of the forehead appear the same. This study and case report of the cosmetic use of botulinum toxin to treat a cosmetic complication of a cosmetic surgery was the first report on the specific treatment of wrinkles and was published in the journal
Plastic and Reconstructive Surgery in 1989. Editors of the journal of the American Society of Plastic Surgeons have clearly stated "the first described use of the toxin in aesthetic circumstances was by Clark and Berris in 1989." J. D. and J. A. Carruthers also studied and reported in 1992 the use of botulinum toxin type-A as a cosmetic treatment.[78] They conducted a study of participants whose only concern was their glabellar forehead wrinkle or furrow. Study participants were otherwise normal. Sixteen of seventeen participants available for follow-up demonstrated a cosmetic improvement. This study was reported at a meeting in 1991. The study for the treatment of
glabellar frown lines was published in 1992. This result was subsequently confirmed by other groups (Brin, and the Columbia University group under Monte Keen). The FDA announced regulatory approval of botulinum toxin type A (Botox Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines) in 2002 after extensive clinical trials. Well before this, the cosmetic use of botulinum toxin type A became widespread. The results of Botox Cosmetic can last up to four months and may vary with each patient. The US
Food and Drug Administration (FDA) approved an alternative product-safety testing method in response to increasing public concern that
LD50 testing was required for each batch sold in the market. Botulinum toxin type-A has also been used in the treatment of
gummy smiles; the material is injected into the hyperactive muscles of upper lip, which causes a reduction in the upward movement of lip thus resulting in a smile with a less exposure of
gingiva. Botox is usually injected in the three lip elevator muscles that converge on the lateral side of the ala of the nose; the
levator labii superioris (LLS), the
levator labii superioris alaeque nasi muscle (LLSAN), and the
zygomaticus minor (ZMi).
Chronic pain William J. Binder reported in 2000 that people who had cosmetic injections around the face reported relief from chronic headaches. This was initially thought to be an indirect effect of reduced muscle tension; however, the toxin is now known to inhibit the release of peripheral nociceptive neurotransmitters, thereby suppressing the central pain processing systems responsible for
migraine headaches. ==Society and culture==