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Botulinum toxin is the most toxic substance known. Botulism, a rare disease, occurs naturally as four syndromes: (1) food-borne illness due to ingestion of toxin in contaminated food; (2) wound infection due to wound colonization by toxigenic clostridia with in situ toxin production; (3) infant botulism due to colonization of the infant intestine by toxigenic clostridia with in situ toxin production; and (4) adult intestinal toxemia, a rare form of colonization with similarities to infant botulism. In addition to these recognized natural forms, botulism has been reported in association with injections of botulinum toxin for cosmetic or therapeutic purposes and after inhalation of aerosolized botulinum toxin. Botulism is caused by the toxin's inhibition of acetylcholine release at the neuromuscular junction through an enzymatic mechanism. All forms of botulism manifest as a distinct clinical syndrome of symmetric cranial nerve palsies followed by descending symmetric flaccid paralysis of voluntary muscles, which may progress to respiratory compromise and death. The mainstays of therapy are meticulous intensive care and timely treatment with antitoxin, which may limit the extent of paralysis. Rapid clinical diagnosis is critical for decisions about treatment.

Etiology and Pathogenesis

Botulinum toxin–producing clostridia are anaerobic gram-positive organisms that form subterminal spores and are ubiquitous in the environment. The hardy spores survive environmental conditions and ordinary cooking procedures. Toxin production, however, requires spore germination, which occurs only with a rare confluence of circumstances: an anaerobic atmosphere, a pH of >4.5, low salt and sugar concentrations, and temperatures of 4–120°C. Although commonly ingested, spores do not normally germinate in the intestine.

The various species of toxigenic clostridia—C. botulinum groups I, II, and III; C. argentinense (toxin type G); C. baratii (toxin type F); and C. butyricum (toxin type E)—can be differentiated on the basis of phenotypic characteristics, including specific biochemical properties and morphologic appearance on egg yolk agar. Strains of a given species can be distinguished by the antigenic specificity of the botulinum neurotoxin they produce; certain strains may produce more than one toxin serotype.

The seven identified toxin serotypes (A, B, C, D, E, F, and G) are antigenically distinct but structurally similar (∼150-kDa zinc-endopeptidase proteins consisting of a 100-kDa heavy chain and a 50-kDa light chain). Whether ingested, inhaled, or produced in the intestine or a wound, botulinum neurotoxin enters the vascular system and is transported to peripheral cholinergic nerve terminals, including neuromuscular junctions, postganglionic parasympathetic nerve endings, and peripheral ganglia. The central nervous system probably is not involved. Steps in neurotoxin activity include (1) heavy-chain binding to nerve terminals, (2) internalization in endocytic vesicles, (3) translocation to cytosol, and (4) light-chain serotype-specific cleavage of one of several proteins involved in the release of the neurotransmitter acetylcholine. Inhibition of acetylcholine release by any of the seven toxin serotypes results in characteristic flaccid paralysis. Recovery follows sprouting of new nerve terminals.

Toxin serotypes A, B, E, and (rarely) F cause human disease. ...

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