Expanding use of botulinum toxin

Abstract

Botulinum toxin type A (BTX-A) is best known to neurologists as a treatment for neuromuscular conditions such as dystonias and spasticity and has recently been publicized for the management of facial wrinkles. The property that makes botulinum toxin type A useful for these various conditions is the inhibition of acetylcholine release at the neuromuscular junction. Although botulinum toxin types A and B (BTX-A and BTX-B) continue to find new uses in neuromuscular conditions involving the somatic nervous system, it has also been recognized that the effects of these medications are not confined to cholinergic neurons at the neuromuscular junction. Acceptors for BTX-A and BTX-B are also found on autonomic nerve terminals, where they inhibit acetylcholine release at glands and smooth muscle. This observation led to trials of botulinum neurotoxins in various conditions involving autonomic innervation. The article reviews the emerging use of botulinum neurotoxins in these and selected other conditions, including sialorrhea, primary focal hyperhidrosis, pathological pain and primary headache disorders that may be of interest to neurologists and related specialists.

Introduction

Botulinum toxin type A (BTX-A) is best known to neurologists as a treatment for neuromuscular conditions such as dystonias and spasticity and has recently been publicized for the management of facial wrinkles. The property that makes botulinum toxin type A useful for these various conditions is the inhibition of acetylcholine release at the neuromuscular junction [1]. The efficacy of BTX-A without systemic side effects has led to the rapid development of its application in various conditions in addition to dystonia and spasticity, including hypersecretory disorders, tics, tremor, stuttering, different pain syndromes, detrusor sphincter dyssynergia or overactivity and gastrointestinal smooth muscle/sphincter spasms [2], [3], [4], [5]. Following local injection into muscles, the toxin enters the nerve terminal via endocytosis, interacts with intracellular proteins (SNARE proteins) and inhibits the vesicular release of the acetylcholine (Ach) neurotransmitter at the neuromuscular junction [1], [6]. Inhibition of Ach produces chemical denervation and paralysis of the striated muscles. Paralysis usually peaks 2 weeks after the injection. Because of the molecular turnover within the neuromuscular junction and neuronal sprouting, neuronal activity begins to return at 3 months, with restoration of complete function at approximately 6 months [7].

BTX-A is 1 of 7 botulinum neurotoxin serotypes known alphabetically as types A to G [8]. Although these toxins have different intracellular targets, their biological activity at the neuromuscular junction is similar. Of these serotypes, only A and B are currently available as commercial preparations [9]. Types C and F have also been used in humans, but only on an experimental basis [10], [11]. The first commercial preparation of botulinum neurotoxin to be used clinically was based on the A serotype (Botox®), and this product continues to be used in many countries throughout the world. Another preparation based on the A serotype (Dysport®) was later introduced in several countries and may become available in the United States within several years. In the year 2000, a product based on the B serotype (Myobloc®/Neurobloc®) became commercially available. Although all of these formulations inhibit acetylcholine release, they do so at different doses [7], [9], [12]. Thus, all of these products are used clinically at different unit doses that may vary up to several orders of magnitude [9].

Although botulinum toxin types A and B (BTX-A and BTX-B) continue to find new uses in neuromuscular conditions involving the somatic nervous system, it has also been recognized that the effects of these medications are not confined to cholinergic neurons at the neuromuscular junction [13], [14]. Acceptors for BTX-A and BTX-B are also found on autonomic nerve terminals, where they inhibit acetylcholine release at glands and smooth muscle [15]. This observation led to trials of botulinum neurotoxins in various conditions involving autonomic innervation [16], [17], [18]. The rest of this article considers the emerging use of botulinum neurotoxins in these and selected other conditions that may be of interest to neurologists and related specialists (Table 1).