Botulinum Toxin

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Botulism is most commonly caused by ingestion of a neurotoxin produced by Clostridium botulinum in improperly canned food. Poisoning may also occur after wound contamination with the organism. Infant botulism may occur when spores of the organism germinate and manufacture the toxin in the intestinal tract of infants. Botulinum toxin works by inhibiting ACh release at all cholinergic synapses.

Botulinum toxins are classified into seven antigeni-cally distinct types, A through G. Each consists of a polypeptide chain of about 150,000 daltons. All but one is nicked by trypsin-type enzymes to yield a light and heavy chain linked by a disulfide bridge. One end of the heavy chain mediates binding to the nerve terminal, and the other initiates internalization of the toxin. The light chain produces the intracellular inhibition of ACh release. This involves a Zn++-dependent endopeptidase action to cleave synaptic target proteins that control vesicle docking and fusion with the prejunctional membrane.

Neuromuscular paralysis occurs 12 to 36 hours after ingestion of the toxin. Early symptoms include diplopia, dysphagia, and dysarthria. Paralysis may descend to include proximal and limb muscles and result in dyspnea and respiratory depression. The toxins do not cross the placental barrier but do enter the central nervous system (CNS). Pupil size may or may not be normal, but mental and sensory functions are not impaired. Recovery from paralysis requires days to weeks.

Reliable antidotes for botulism are not available. In some cases, anticholinesterase drugs may improve muscle strength, albeit temporarily. Guanidine and 4-aminopyri-dine also have limited usefulness. Management depends primarily on supportive measures, such as administering antitoxin and maintaining respiration.

Botulinum toxin is used clinically in the treatment of blepharospasm, writer's cramp, spasticities of various origins, and rigidity due to extrapyramidal disorders. It is also used to treat gustatory sweating and cosmetically to decrease facial wrinkles. Botulinum toxin A (Botox, Oculinum) injected intramuscularly produces functional denervation that lasts about 3 months. Clinical benefit is seen within 1 to 3 days. Adverse effects range from diplopia and irritation with blepharospasm to muscle weakness with dystonias.

Botulinum toxin is the most toxic substance known. One gram of crystalline toxin adequately dispersed can kill a population of a million people, so its use in bioter-rorism is a possibility. The toxin can be introduced through inhalation or ingestion but not through dermal exposure. The threat of mass inhalation poisoning is limited by the ability or inability to aerosolize the toxin for widespread dispersion. Contaminating the water or food supply is also a possibility, although the toxin is degraded by standard water treatment and by heating of foods to 85°C (185°F) for 5 minutes. Prior immunization with toxoid vaccine is advisable for personnel at risk, but prophylactic administration of trivalent equine antitoxin is not recommended.

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