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Home , Botulism

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 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 into the synaptic cleft. Botulism occurs from consumption or of preformed or growth of 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, , mydriasis, dysphagia, and ), and with normal sensation and mentation. Treatment is aimed at 1) maintaining via intubation and , 2) stop- ping progression of weakness by administration of botulinum (equine trivalent botulinum antitoxin for adults and botulism immune-globulin intravenous-human for infant botulism), and 3) preventing complications from weeks of 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 for years.

Introduction Botulism is a descending, symmetric, 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 at their synapses. lism have been recognized, and rare cases of botulism Human mainly occurs from consumption of have been caused by toxigenic Clostridium butyricum preformed botulinum toxin (foodborne botulism) and and . 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 . 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 that is contaminated ) 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

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. is absent. , 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, IN ADULTS and the cholinergic parasympathetic 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 will not allow coloniza- Irrespective of the route of entry of botulinum toxin tion of C. botulinum. 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 , 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 . 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 (no defeca- , and salsa or relish. Rare outbreaks have tion for 3 or more days), lethargy, (floppy come from 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 1. Botulinum toxin blocks release of acetylcholine at synapse.

Figure 2. Foodborne botulism signs.

botulism is 4 to 6 weeks, with cases of botulism type A paralysis, the total dose inoculated is insufficient being longer that type B. With early diagnosis and good to cause severe systemic paralysis. The adult LD50 of supportive management, the mortality rate is below botulinum toxin is estimated to be about 3000 U, 2%. [4••,9,10]. After clinical recovery from infant whereas therapeutic botulinum doses rarely exceed 400 botulism, the infant may continue to shed both toxin U [13]. However, a few cases of mild generalized and C. botulinum in their stool for several months. weakness have been associated with prior therapeutic injections of botulinum toxin [14]. In treatment of IATROGENIC BOTULISM cervical dystonia, 20% of patients noted dysphagia, Botulinum A and B are widely used as thera- excessive neck muscle weakness, or voice changes likely peutic and cosmetic medicines [4••,12]. Although the caused by the spread of the toxin from the injected sites doses administered are sufficient to cause local muscle to other neck muscle. 26 CNS Infections

Figure 3. Infant botulism signs.

INHALATIONAL BOTULISM frequency nerve stimulation (20 to 50 cycles per Rare cases of inhalational botulism have been reported second), facilitation or an incremental increase in the in individuals purifying the toxin [3••], and experimen- amplitude of the compound muscle tal animal studies confirm that inhalation of the toxin over baseline occurs [6,15]. If the repetitive nerve does produce disease. These studies suggest that the stimulation remains normal in a suspected case of time from human exposure to symptoms would be 12 botulism, single fiber may demon- to 72 hours, and the symptoms would be identical to strate increased jitter and impulse blocking, even in foodborne botulism. clinically normal muscles [16]. Confirmatory tests for botulism can be performed DIAGNOSIS at the Centers for Disease Control and Prevention or When there is a typical clinical picture, especially if state health laboratories by the detection of botulinum several patients present with similar signs suggesting a toxin or growth of C. botulinum. Serum, gastric aspirate, common source outbreak, the diagnosis is straight- stool, and suspected foods can be inoculated into mice forward. In wound botulism, there is often, but not (botulism mouse inoculation test) to detect the always, evidence of a skin infection. The major differen- presence of botulinum toxin and to determine the toxin tial diagnoses for foodborne botulism include Guillain- type. Stool, wound material, gastric aspirate, and Barré syndrome, , tick paralysis, suspected food can be inoculated into anaerobic culture diphtheritic polyneuropathy, poliomyelitis, organo- media to isolate C. botulinum. Clinical samples for phosphate intoxication, and nerve agent poisoning. testing should be refrigerated (freezing reduces the Helpful distinguishing tests include a Tensilon test with chance of isolating C. botulinum) and transported prefera- intravenous injection of chloride (myas- bly by anaerobic transport ice pack. In approximately thenia gravis), measurement of cholinesterase blood two thirds of clinically diagnosed botulism patients, levels (organophosphate or nerve agent intoxication), either botulinum toxin or C. botulinum can be found and cerebrospinal fluid examination (Guillain-Barré [2••,6]. However, isolation of C. botulinum, but not syndrome and poliomyelitis). botulinum toxin, from suspected food is inconclusive. Nerve conduction studies assist in making the Because of the minute amount of toxin exposure in diagnosis. After low frequency stimulation of a botulism, the patient will not make an peripheral nerve, the amplitude of compound muscle response to the toxin during convalescence. Thus, no action potential is abnormally low. After high serologic test is available. Botulism Davis 27

Treatment Management of foodborne, wound, and inhalational botulism Immediate care • Early diagnosis, frequent monitoring, and quality supportive care are essential. • No isolation requirements exist, because the patient is not infectious. • All botulism patients should be hospitalized and placed where excellent nursing and continuous monitoring is available (usually in an intensive care unit). Because respiratory failure can progress quickly, evaluations by nursing should be performed as often as every 10 to 15 minutes once clinical signs appear. Approximately one quarter of patients with food- borne botulism and two thirds of patients with wound botulism require ventilator support. • Clinicians should determine if the patient has pre-existing pulmonary problems (such as chronic obstructive pulmonary disease, asthma, or obesity) that could hasten respiratory failure. Sedating drugs should be avoided when possible. • Frequent neurologic examinations are required with attention to the patient’s ability to breathe, swallow, move limbs, and cough. Appropriate supportive care should be instituted if neurologic problems develop. • Pulmonary functions should be monitored frequently via bedside spiro- metry. Monitoring oxygen desaturation (by pulse oximetry) and respiratory rate may not be sufficient to predict impending respiratory failure. Oxygen desaturation, as measured by arterial blood gases, or pulse oximetry or a labored, elevated respiratory rate may not develop until just before respiratory failure. Repeated measurements of vital capacity are helpful. When the vital capacity falls below 30% of predicted, elective intubation and mechanical ventilation should be considered, particularly if the paraly- sis rapidly progresses and there is hypoxemia with absolute or relative hypercarbia on arterial blood gas measurements. If available, serial measurements of maximum static inspiratory pressure also may predict impending respiratory failure. • Cardiac monitoring may identify severe tachycardia and cardiac arrhyth- mias requiring treatment. • Administration of trivalent (type A, B, and E) botulism antitoxin should be started as soon as possible without waiting for laboratory confirmation. The antitoxin eliminates circulating toxin, but does not remove toxin that has already entered the . Therefore, the antitoxin will not reverse paralysis that has occurred, but will prevent progression of the weakness and may shorten hospitalization [17, Class III]. The antitoxin is produced in horses. Each 10-mL vial contains about 7000 IU of each botulinum type, and sufficiently neutralizes circulating toxin found in all forms of botulism. The half-life of the circulating antitoxin is 5 to 7 days. • Controversy exists about attempting to remove unabsorbed botulinum toxin from the gut. Most studies show absorption of botulinum toxin occurs mainly in the upper intestine, and how much toxin actually is absorbed in the colon is unclear. If the food suspected of containing botulinum toxin was recently consumed and the patient does not have an ileus, nonmagne- sium-containing cathartics (elevation of serum magnesium levels may worsen the neuromuscular blockade) or can remove unabsorbed toxin from the gut [6]. 28 CNS Infections

• Nasogastric feeding (once bowel sounds are established) often is required for nutrition and fluids, because dysphagia is common and often severe. An intravenous line may be needed early in the course until bowel sounds return. • Mental status abnormalities may reflect hypoxia or anxiety, because botulism does not affect mental status. • Attention regarding comfort and positioning should be given to a paralyzed patient on mechanical ventilation, because botulism does not impair sensation. • Antibiotics have no effect on botulinum toxin and, therefore, have no value in foodborne or inhalational botulism. • In wound botulism, however, antibiotics and surgical debridement are considered valuable in eradicating the C. botulinum infection [6,7]. The suspected wound should be surgically debrided. Administration of penicil- lin G (10 to 20 million U per intravenously for 7 to 10 days) should be given preferably after administration of the antitoxin as lysis of C. botulinum by releases more botulinum toxin. Metronidazole may be a suitable alternative.

Chronic care of severe cases • Once a patient begins mechanical ventilation, he or she will likely require ventilator support for several weeks to 3 months. Thus, excellent nursing care minimizes the risk of pulmonary and other complications. • Clinicians should consider elective tracheostomy after 1 to 2 weeks of mechanical ventilation to minimize damage and scarring to vocal cords and trachea. • Aminoglycosides and clindamycin antibiotics will exacerbate the neuro- muscular blockade [19]. Thus, should aspiration or lobar pneumonia develop, these antibiotics should be administered only if there are no other alternatives. • Attention to insure adequate nutrition and fluid balance is important when patients cannot feed themselves. • Care must be given in initiating oral feeding, because the patient is still prone to dysphagia, especially if tired. A soft mechanical diet may be required for weeks to months in some patients. • Physical therapy helps with early passive range of limb motion in the paralyzed patient and later muscle strengthening exercises help recovery. • Patients often complain of marked fatigue, exercise intolerance, general weakness, dry mouth, and that may persist for over 1 year [20]. However, they may have normal muscle strength. Patients seldom are able to return to work full-time for months.

Management of infant botulism • Early intubation and mechanical ventilation should be considered if the infant has a weak cry, swallow, cough, or gag, and demonstrates marked weakness of head and body. Tachypnea, hypercarbia, and hypoxemia are often late signs of impending respiratory failure [4••,9,10,11••]. Careful selection of tube size minimizes tracheal complications. Elective intubation may also be performed to protect the infant’s airway, even if mechanical ventilation is not required. Approximately 75% of infants are intubated. Botulism Davis 29

• Intubation is often required for 3 to 5 weeks. Extubation should be consid- ered when the infant has sustained motion against gravity and has return of gag and cough reflexes. • Elective tracheostomy should be considered if intubation is prolonged, but the rate varies for each institution. • The infant’s stool should be autoclaved, because it will contain C. botulinum spores and toxin. However, isolation is not necessary. Meticulous hand washing is indicated to prevent accidental spread of spores to other hospitalized infants. • Elevation of the head of the mattress (20º to 30º) may improve the infant’s ability to swallow their secretions. • Neck flexion that can compromise breathing when positioning the infant should be avoided. • Nutrition should be provided via a nasogastric tube when bowel sounds are present at a rate of about two thirds that of a similar healthy child. • Serum needs to be monitored, because inappropriate secretion of antidiuretic hormone may occur with secondary hyponatremia sufficient to cause seizures. • Weight, fluids, and electrolytes should be monitored, and appropriate corrections should be made as indicated. • Emptying the bladder using the Credè maneuver often precludes the need for a urinary catheter. • Enemas and cathartics have not been shown to be beneficial. • Administering antibiotics to eliminate C. botulinum from the gut have not shown to shorten the clinical course. However, complications, such as otitis media (in approximately 30% of patients), pneumonia (15%), and (6%), may require antibiotics. Aminoglycosides and clindamycin should be avoided if possible, because they worsen the neuro- muscular blockade [19]. • Human antiserum to botulinum toxin should be administered. California, under the sponsorship of the Orphan Drug Program of the US Food and Drug Administration, has produced a human antiserum from adult volun- teers immunized with botulinum . The human antiserum has a half- life of 1 month, but is effective in neutralizing botulinum toxin for about 6 months. In a 5-year placebo-controlled, randomized clinical trial, a single intravenous dose of botulism immune-globulin intravenous demonstrated significant reduction in hospitalization from 5.5 weeks to 2.5 weeks, and a two thirds reduction in the rate of intubation [11••, Class I].

Prevention of botulism • To denature botulinum toxin, heat to 85ºC for 5 minutes. • To kill C. botulinum spores, heat under pressure to 116ºC for 15 minutes. Thus, home- food by boiling (100ºC) and not via a pressure- cooker is unlikely to kill all C. botulinum spores. • Do not feed honey to infants under age 12 months, because it may contain C. botulinum spores that can colonize the gut [4••,11••]. • An investigational pentavalent (ABCDE) botulinum toxoid is available from the Centers for Disease Control and Prevention for laboratory workers at high risk for exposure, and is available from the military to immunize certain military personnel for protection against an enemy or bioterrorist exposure to aerosols of botulinum toxin. The toxoid is usually administered at 0, 2, and 12 weeks followed by a yearly booster. The vaccine has no value after toxin exposure to prevent disease [3••]. 30 CNS Infections

Pharmacologic treatment Trivalent equine botulinum antitoxin Standard dosage New Centers for Disease Control and Prevention recommendations are that one 10-mL vial (not two) should be administered. The antitoxin vial should be diluted 1:10 in 0.9% saline solution, and administered by slow intravenous infusion [3••, Class III]. The antitoxin should be administered as soon as possible without waiting for labora- tory confirmation. Contraindications The antitoxin should not be given to individuals with known allergies to equine products. Main drug interactions None known. Main side effects Allergy to equine antitoxin occurs. The old higher dose two-vial regimen caused about 9% incidence of urticaria, , or other reactions suggestive of [18]. In 2% of recipients, anaphylaxis occurred, usually in 10 minutes of receiving the antitoxin. The incidence of allergic reactions appears lower with the new one-vial recommendation, but experience is limited. Screening for hypersensitivity is problematic. Patients can be given a small intradermal challenge dose of the equine antitoxin before receiving the full dose. If a wheal and flare develop, it is possible to desensitize the patient over 4 hours. However, skin testing may not prevent allergic reactions. In one review of 268 cases, more than half of patients who had acute allergic reactions had negative skin tests and some individuals developed acute reactions from the skin test dose [18]. Diphenhydramine and epinephrine should be immediately available during the antitoxin administration should allergic reactions develop. Special points Hospitals do not carry botulinum antitoxin. To obtain the antitoxin, contact local and state health departments. If they are unavailable, the Centers for Disease Control and Prevention can be telephoned at 404-639-2206 or by the emergency after hours numbers 404-639-2888 or 770-488-7100. Cost/cost effectiveness No information available.

Botulism immune-globulin intravenous-human for infant botulism Standard dosage The state of California produces botulism immune-globulin intravenous-human under a special agreement with the US Food and Drug Administration as an orphan drug. A one-time dose of 50 mg/kg is given intravenously to the infant. The botulism immune globulin comes in 100-mg vials. Contraindications None known. Main drug interactions None known. Main side effects To date, there have been no major adverse reactions in infants. A few infants do develop a transient mild rash after administration. Special points Requests for human botulinum immune-globulin should be made to California Department of Health Sciences 24 hours per day by calling 510-540-2646. Human botulinum immunoglobulin is available only for infant botulism and not for other types of botulism. Cost/cost effectiveness The present cost is $1560 per total infant dose but this is likely to increase. The California Department of Health estimates total hospital costs for a case of infant botulism to be about $75,000 and that the use of botulism immune-globulin may reduce the cost by $30,000 from a shortened hospitalization. Botulism Davis 31

References and Recommended Reading

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