Botulism Larry E. Davis, MD Address Neurology Service, New Mexico VA Healthcare System and the University of New Mexico School of Medicine, 1501 San Pedro Drive, SE, Albuquerque, NM 87108, USA. E-mail: [email protected] Current Treatment Options in Neurology 2003, 5:23–31 Current Science Inc. ISSN 1092-8480 Copyright © 2003 by Current Science Inc. Opinion statement Botulinum toxin is the most potent toxin known to humans and as little as 100 ng can be lethal. The toxin blocks peripheral cholinergic neurotransmission at the neuromuscu- lar junction and cholinergic autonomic nervous system by introducing an endopeptadase enzyme into the presynaptic side of the synapse. The endopeptadase cleaves acetylcho- line vesicle docking proteins that are required for the synapse to release acetylcholine into the synaptic cleft. Botulism occurs from consumption or inhalation of preformed botulinum toxin or growth of Clostridium botulinum bacteria in the infant gastrointesti- nal tract or within a wound. Growth of C. botulinum in the immature gut or wound will release botulinum toxin that reaches the circulation. All forms of botulism cause progressive weakness, bulbar signs (blurred vision, diplopia, mydriasis, dysphagia, and dysarthria), and respiratory failure with normal sensation and mentation. Treatment is aimed at 1) maintaining respiration via intubation and mechanical ventilation, 2) stop- ping progression of weakness by administration of botulinum antitoxin (equine trivalent botulinum antitoxin for adults and botulism immune-globulin intravenous-human for infant botulism), and 3) preventing complications from weeks of paralysis with good supportive care. The source of the botulinum toxin should be identified to prevent additional cases. Patients can recover normal muscle strength within weeks to months, but usually complain of fatigue for years. Introduction Botulism is a descending, symmetric, flaccid paralysis of neurotoxins, with humans intoxicated mainly by caused by interrupted transmission of peripheral motor types A, B, or E [2••]. Rare cases of type F human botu- and cholinergic autonomic nerves at their synapses. lism have been recognized, and rare cases of botulism Human disease mainly occurs from consumption of have been caused by toxigenic Clostridium butyricum preformed botulinum toxin (foodborne botulism) and and Clostridium baratii. Clostridium botulinum grows growth of Clostridium botulinum in the gastrointestinal best in an anaerobic, warm (approximately 40ºC), low tract of infants with subsequent absorption of the toxin acid (pH greater than 4.6), watery environment that (infant botulism). However, cases of wound botulism lacks food preservatives. are increasing, mainly from heroin addicts who Botulinum toxin is the most potent biologic inoculate C. botulinum spore-contaminated heroin toxin known. The 50% lethal dose (LD50) for humans subcutaneously (“skin popping”). Potentially, botuli- has been calculated to be 0.1 µg for intravenous or num toxin aerosols could be used as a bioweapon to intramuscular inoculation, 0.7 µg for inhalational produce inhalational botulism. exposure, and 70 µg for oral exposure [2••]. Thus, the In 1897, van Ermengem [1] established the lethal dose for inhalation is 100-fold less than from oral bacterial etiology of botulism after his investigation of consumption, which makes it a potential bioterrorist foodborne outbreak in Belgium from contaminated agent. In spite of its potency, natural botulinum toxin raw ham. The bacterium, C. botulinum, was a spore- is easily denatured. Heating to 85ºC (as in cooking forming anaerobic Gram-positive bacillus that is contaminated foods) and exposure to sunlight and commonly found in soil and water sediment around chlorine (as present in lakes or city water systems) the world. Clostridium botulinum produces seven types denatures the toxin [3••,4••]. 24 CNS Infections Recently, the mechanism by which botulinum toxin period. The major clinical signs of foodborne botulism paralyzes has become understood. Botulinum toxin is a are considered the “big D” (Fig. 2). In general, the 150-kDa molecule that is comprised of a heavy chain earliest symptoms are disturbed, blurred vision (from loss (100 kDa) and a light chain (50 kDa) held together by a of accommodation), dysphagia, and descending weak- disulfide bond. In foodborne botulism, the toxin is ness. Over the several hours to few days after consump- protected from stomach acid by other proteins released tion, the signs progress. The patient retains a normal by C. botulinum that loosely attach to the toxin. In the mental status and normal sensation. The hemogram, upper intestine, the toxin is actively transported serum electrolytes, liver function studies, and renal through intestinal lining cells by receptor-mediated studies are normal. Fever is absent. Cerebrospinal fluid, transcytosis [5••]. On reaching the blood stream, toxin neuroimaging, and electroencephalogram also are circulates until it reaches a peripheral acetylcholine normal. The case fatality rate is approximately 15% [2••]. synapse (the toxin does not cross the blood-brain barrier, so it does not affect brain cholinergic synapses). WOUND BOTULISM The heavy chain possesses a highly specific domain that Until recently, wound botulism was uncommon (one or attaches to the presynaptic side of the synapse (Fig. 1). two cases per year), and resulted from crush wounds, The toxin is then internalized into the cytoplasm via an post-surgery, and sinusitis after intranasal cocaine use in endocytotic vesicle. As the pH in the vesicle lowers, the which C. botulinum spores replicated in an anaerobic toxin reconfigures and the heavy chain penetrates the environment to produce toxin that was absorbed [7]. In vesicle wall, which allows the light chain to pass the western US, especially California, cases associated through the vesicle wall and become free into the with heroin “skin popping” have appeared. Black cytoplasm. The light chain, a zinc containing endo- tar heroin, mainly from Mexico, can be contaminated peptidase enzyme, subsequently cleaves docking with C. botulinum spores that are then subcutaneously proteins called SNARE proteins. SNARE proteins enable inoculated with the heroin, resulting in wound vesicles containing quantal amounts of acetylcholine to botulism [8••]. In the past few years, up to 35 cases per fuse with the presynaptic membrane to release acetyl- year have been reported from California [8••]. The choline into the synaptic cleft. Thus, botulinum toxin clinical signs are similar to foodborne botulism (Fig. 2). blocks stimulus-induced and spontaneous quantal The case-fatality rate is approximately 15%. acetylcholine release on the presynaptic side of the cholinergic synapse. As a consequence of the light-chain INFANT BOTULISM AND GUT COLONIZATION cleaving SNARE proteins, the muscle fails to contract, INFECTION IN ADULTS and the cholinergic parasympathetic nerve fails to Each year, there are nearly 70 cases of infant botulism function. The resulting synaptic failure continues for reported to the Centers for Disease Control and Preven- weeks to 6 months. The high potency of botulinum tion in Atlanta, GA. Infant botulism occurs only in toxin results from its high specificity to attach only to a children during the first 12 months of life, with a peak few membrane sites and its enzymatic activity that at 2 to 3 months [4••,9,10,11••]. After that age, the cleaves critical proteins needed for synaptic function. normal gastrointestinal tract will not allow coloniza- Irrespective of the route of entry of botulinum toxin tion of C. botulinum. Breastfeeding does not prevent into the body, the resulting clinical picture is similar. infant botulism, because approximately 70% of However, the clinical setting of the intoxication differs. cases had been breast-fed. Adults with abnormal gastro- The major forms of botulism are discussed herewith. intestinal tracts from chronic antibiotics, achlorhydria, and intestinal surgery may also develop colonization FOODBORNE BOTULISM of C. botulinum, C. butyricum, and C. baratii with In recent years, there have been approximately 1000 subsequent absorption of the toxin. cases of foodborne botulism reported annually around The infant consumes C. botulinum spores by eating the world, with approximately 32 cases occurring unrecognized spore-containing food substances, dust, annually in the US [2••,6]. In the continental US, or honey. In the immature cecum to rectum, the spores botulinum toxin types A and B predominate, although germinate, colonize the gut, and produce botulinum type E predominates in Alaska. The most common toxin that is slowly absorbed. These infants develop an source is from home-canned or home-processed low- illness that progresses over hours to 20 days (mean acid foods, such as vegetables, chili peppers, meat, 4 days) that is characterized by constipation (no defeca- fermented fish, and salsa or relish. Rare outbreaks have tion for 3 or more days), lethargy, hypotonia (floppy come from garlic in oil and from baked potatoes in infant), poor crying, poor feeding, and loss of head aluminum foil that are held at room temperature. control (Fig. 3) [4••,10]. The time from toxin consumption to first symptom Treatment of infant botulism differs from food- ranges from 24 to 108 hours with the peak at 48 hours. borne and wound botulism, and is discussed separately The more toxin consumed, the shorter the “incubation” in this review. The average hospitalization for infant Botulism Davis 25 Figure