Botulinum toxin treatment of neurologic disorders

Historical note and nomenclature
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By Charles E Argoff MD and Howard S Smith MD

Botulinum toxin is a potent neurotoxin that is produced by the gram-positive, spore-forming, anaerobic bacterium, Clostridum botulinum. Botulinum toxins are neurotoxins produced by the gram-positive, spore-forming, anaerobic bacteria, Clostridium botulinum, as well as C. butyricum, C. baratii, and C. argentinense (Schantz and Johnson 1992; Johnson 1999). These toxins are the most deadly human neurotoxins known. Clinically, botulism can occur following ingestion of contaminated food or may result from a wound infection. The clinical signs of botulism include limb paralysis, facial weakness, ophthalmoplegia, dysarthria, dysphagia, dyspnea progressing to respiratory arrest, constipation progressing to ileus, and urinary retention (Davis 1993). C. botulinum produces 7 antigenically (immunologically) distinct neurotoxins: A, B, C1, D, E, F, and G. These neurotoxins block neuromuscular transmission, resulting in both skeletal and smooth muscle paralysis. Botulinum toxin has no effect on sensory neurons.

In an effort to find a nonsurgical treatment for strabismus, Edward J. Schantz and Alan B. Scott first began experimenting with botulinum toxin type A to weaken skeletal muscle in rhesus monkeys (Schantz and Johnson 1997), leading to human studies in patients with strabismus and facial spasms (Scott 1981). Further studies then began in other disorders of muscle hyperactivity, such as cervical dystonia (spasmodic torticollis) and laryngeal dystonia (spasmodic dysphonia). In December 1989, the United States Food and Drug Administration approved the use of botulinum toxin type A for use in strabismus, blepharospasm, hemifacial spasm, and other disorders of the seventh cranial nerve in patients 12 years of age or older (Schantz and Johnson 1992). In 2000, botulinum toxin type A received approval for use in cervical dystonia, and in 2001 botulinum toxin type B became the second commercially available botulinum toxin in the United States; it is approved for cervical dystonia (Lew et al 2000).

There are 7 known immunologically distinct serotypes of botulinum toxin: types A, B, C1, D, E, F, and G. Only types A and B have been developed for commercial use in routine clinical practice. Two type A preparations, BOTOX® (Allergan, Inc. Irvine, CA) and Dysport® (Ipsen Ltd., Berkshire, United Kingdom) have been developed, but only BOTOX® is available in the United States at this time. Type B is currently commercially available as Myobloc® in the United States and as Neurobloc® in Europe. Each of these neurotoxins are proteins and vary with respect to molecular weight, mechanism of action, duration of effect, and adverse effects. Each toxin is initially synthesized by the bacteria as a single chain polypeptide. Bacterial proteases then “nick” both type A and type B proteins, resulting in a di-chain structure consisting of 1 heavy and 1 light chain. Type A is nicked more than Type B, and there is less than a 50% homology between the 2 toxins (Setler 2002).