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Kevin Lohenry is Program Director and Assistant Professor, and Kristin Foulke is an adjunct clinical faculty member, both at the Midwestern University Physician Assistant Program, Glendale, Ariz. The authors have indicated no relationships to disclose relating to the content of this article.

Clostridium botulinum is a spore-forming, gram-positive anaerobic bacillus found in the soil and in sediments of streams, lakes, and coastal waters throughout the world. Botulinum toxin is one of the clostridial neurotoxins, and its extreme neurotoxicity—it is one of the most poisonous substances known—makes it one of the first agents to be considered as a biological weapon.¹ A very small amount of the toxin could cause widespread mortality: the LD50—the dose that is lethal to 50% of the exposed population—is 1 ng/kg.¹

The neurotoxin produced by C botulinum has been encountered in the canning or preservation of foods, although this occurs less commonly now with modern canning technology.² E. van Ermengem first described the origin of C botulinum in 1897 while investigating a foodborne outbreak in Ellezelles, Belgium.³ The word botulism comes from the Latin botulus, which means sausage. Home-fermented sausages caused many of the early cases of botulism.³ An average of 110 cases of botulism are reported annually in the United States, with approximately 70% related to infant botulism and about 25% related to foodborne botulism.⁴ In fact, a recent CDC Health Advisory e-mailed to clinicians in early September reported an outbreak of botulism in Georgia caused by botulinum toxin type A in bottled carrot juice. Three people were affected.

The potential terrorist use of botulinum toxin has led the CDC to classify it as a Category A biological agent, owing to its ability to cause public panic and its potential impact on public health. These categories are designated by the CDC for biological agents to stratify their risks to public health.⁵

Botulinum toxin: The weapon

World War II The initial efforts to weaponize botulinum toxin began during the early part of World War II, when intelligence reports indicated that Germany was attempting to develop the toxin for use against invasion forces. Great Britain was known to have begun developing an extensive biological warfare program during the 1940s. In fact, it was reported that British forces might have used the toxin against Reinhard Heydrich, the head of the Gestapo and Security Service in Germany.¹

The United States explored the use of a weaponized botulinum toxin shortly after World War II.¹ Following reports that Germany had weaponized botulinum toxin, the United States developed more than 1 million doses of botulinum toxoid vaccine, which was intended to protect the allied troops in the event of an attack. Biological weapons research and development was subsequently discontinued by President Richard M. Nixon’s executive order in 1969-1970. The 1972 Biological and Toxin Weapons Convention aligned 103 countries in the discontinuation of offensive biological and chemical weapons programs.⁶

Iraq After the 1990-1991 Persian Gulf War, Iraq reported the production of 19,000 L of concentrated botulinum toxin, of which approximately 10,000 L were loaded into military weapons, including missiles and bombs. The location of this stockpile—and whether it still exists—are subjects of controversy today.

Japan The most recent known attempt to use botulinum toxin came in 1995 from the Japanese cult Aum Shinriky¯o, who had attempted to disperse the toxin in an aerosolized form against United States military installations. Their failure was attributed to faulty microbiological technique, deficient aerosol-generating equipment, and internal sabotage. It is reported that they had obtained their C botulinum from soil they collected in northern Japan.⁶

Pathogenesis of botulism

There are seven distinct serotypes of botulinum neurotoxins labeled A-G. Toxins A, B, E—and, rarely, F—have been linked to human infection.⁶ Pharmacologically, the toxins share similar shape, structure, and mechanism of action. The toxin enters the neuronal cell and prevents the release of the neurotransmitter acetylcholine from presynaptic terminals of the motor neurons in skeletal muscle. This important neurotransmitter is responsible for neuromuscular communication throughout the body. Without acetylcholine, muscular contractions cease, leading to the symmetric descending paralysis pathognomonic of botulism.^7,8

Forms of human botulism

Four forms of human botulism have been reported: foodborne, which occurs from ingestion of preformed toxin in contaminated food; intestinal, which occurs with the ingestion of spores and the subsequent production of toxin in the intestines of infants or adults; inhalational, which may occur as a result of a terrorist act; and wound, which occurs from production of toxin in wounds that have been contaminated by soil that carries the organism. These forms have similar mechanisms of action but different routes of entry.^1,8

Foodborne botulism In adults, A, B, and E toxins are the most commonly reported causes of outbreaks of foodborne botulism. Serotoxin A is more common west of the Mississippi River, and serotoxin B is more common east of the Mississippi. Serotoxin E is not commonly seen but is associated with seafood exposure and is most commonly seen in Alaska.³

The incubation period for foodborne botulism is 18 to 36 hours.⁸ Home canning is strongly associated with outbreaks, although commercially canned foods and restaurant-prepared foods have also been implicated in outbreaks across the country. Heating food to a temperature that exceeds 80°C (176°F) for more than 30 minutes destroys the toxin. Temperatures exceeding 100°C (212°F) destroy it within minutes.⁹

Botulism is typically suspected from clinical signs. Symmetric descending paralysis is a cardinal sign, and it can lead to respiratory failure and death. Cranial nerve involvement almost always marks the onset of symptoms. This can include diplopia, dysarthria, dysphonia, and dysphagia.⁸ Other common symptoms are listed in Table 1.

Intestinal botulism This form of the disease can occur in adults and young children, but it is far more prevalent in infants.¹⁰ The cause is C botulinum colonization of the intestine, with subsequent in vivo toxin production. Infant age at diagnosis is typically 6 weeks to 9 months. Infant botulism is characterized by the onset of constipation, followed by a weakness in sucking, crying, or swallowing. Patients may also exhibit hypotonia and progressive bulbar and extremity muscle weakness. Paralysis progresses to encompass the peripheral and respiratory musculature.¹¹

Intestinal botulism is considered distinct from foodborne botulism because the toxin is not formed before ingestion. The neurotoxin is produced after ingestion, germination, and colonization. Geographically, most cases of infant botulism occur in California, where the average age of victims is 2 to 3 months.¹¹ Honey added to a baby’s bottle is also strongly associated with development of infant botulism. Clinicians should recommend that parents exclude honey from an infant’s diet until the child is older than 1 year.⁸

Inhalational botulism Botulism acquired through respiratory exposure is not a naturally occurring phenomenon. The clinical presentation is similar to that of foodborne botulism, but the route of entry is through a respiratory mechanism. Inhaled botulinum toxin is a potential weapon, and there have been reports of weaponized botulinum toxin in Iraq, the former Soviet Union, and other countries.¹² In 1962, three veterinary personnel were exposed to aerosolized botulinum toxin while disposing of rabbits and guinea pigs. The animals had reportedly been coated with aerosolized type A botulinum toxin.⁶ In addition, there have been reports of a failed terrorist attempt by the Japanese Aum Shinriky¯o doomsday cult to release aerosolized botulinum toxin in Tokyo, Japan, between 1990 and 1995.^6,13 If a terrorist release of spores or toxin were to occur, the epidemiologic survey of the symptoms should eventually lead to the diagnosis of an outbreak.

Wound botulism Another rare form of the disease is wound botulism, which results from the growth of C botulinum spores in a wound that has been contaminated by exposure to soil. Wound botulism is the least common form of botulism in the United States, with only 33 incidents reported between 1943 and 1985.²

Since 1980, there has been an association between wound botulism and illicit drug use. Wound botulism in these instances is thought to occur secondary to needle puncture wounds (such as from IV use of black tar heroin) or to result from nasal and sinus lesions resulting from inhaling cocaine.^14,15 Once spores enter the wound, in vivo toxin production begins. C botulinum spores grow within a nonhealing wound and produce toxin. This toxin then enters the bloodstream and produces a neurologic paralysis that is indistinguishable from that seen in other forms of botulism. The wound may not appear to be acutely infected, but the infection is usually deep. Deep, penetrating traumas provide the perfect medium for replication of the bacilli. This anaerobic environment allows C botulinum to produce toxin with direct access to a readily available blood supply.^14,15

Most cases of wound botulism have been reported in men, in part because men are more often exposed to soil when performing heavy labor or engaged in outdoor hobbies. More IV drug users are also male.

Serotypes A and B account for the majority of wound cases. The wound botulism incubation period is an average of 7 days, with a range of 4 to 14 days.³ If a patient presents with descending paralysis, performing a primary skin survey will uncover any source of wound botulism exposure. The wound should be cultured to reveal any bacteria, but treatment should not be delayed while waiting for the results of wound cultures.¹⁵

The clinical presentation of wound botulism is very similar to that of foodborne botulism. The major difference is the absence of GI symptoms—nausea, vomiting, and diarrhea—because the toxin is not absorbed through the GI tract.³

Diagnosis

Botulinum toxin infection carries significant morbidity and mortality. Diagnosis is based on a history and thorough physical examination. Of course, the awareness of botulism should be high in a time of suspected terrorist acts. If multiple patients in a given area appear with symmetric descending paralysis, this should be immediately reported to the health department. In the event of naturally occurring botulism due to foodborne or wound infection, the diagnosis may be more challenging. Cluster outbreaks of botulism do occur naturally, but it is difficult to identify such clusters before serious illnesses and deaths occur.²

History and differential diagnosis The history is essential in establishing the diagnosis and should include questions about any recent ingestion of home-canned foods and about family members who are ill with similar symptoms. Parents of an affected infant should be asked about the baby’s diet, including about whether honey might have been added to the infant’s bottle. A complete history should also include questions about any recent wounds that have not healed properly.

The results of routine laboratory tests—including a CBC, liver and kidney function tests, urinalysis, and serum electrolyte measures—are usually normal for patients with botulism, whereas they would be abnormal in those with bacterial, viral, or fungal infections. A CSF analysis may show a slightly higher protein level with botulism than with Guillain-Barré syndrome. The result of an edrophonium chloride (Tensilon) test may be falsely elevated in patients with botulism. These patients typically have levels that are less dramatically elevated than in persons with myasthenia gravis. Brain imaging studies are used to rule out stroke in patients with paralysis.^{3,6,8,9,11,16}

Electromyelography (EMG) has shown some promising results in diagnosing botulism and in differentiating it from Guillain-Barré syndrome. Skeletal muscles that have been affected by botulism can show a positive response to repetitive 20- to 50-Hz stimulation.⁶ A case study report suggests that single-fiber EMG may be more helpful than routine EMG.¹⁷ The authors found that results of a routine EMG were unremarkable but that the single-fiber EMG showed elevated jitter time (the degree of variability in the interval between the EMG responses of two single muscle fibers) with the presence of blocks of neuromuscular transmission in the extensor digitorum communis, which helped confirm the suspicion of botulism.¹⁷ EMG is very technician dependent, so the reliability of results varies with the technician’s level of experience and skill.^6,18

It is crucial to remember that delaying treatment of a patient with botulism to wait for culture results could prove deadly.^6,8 Blood, stool, and wound cultures will confirm the diagnosis of botulism toxin exposure, while a mouse neutralization bioassay will give a definitive diagnosis.^16,19

Management

Mechanical ventilation is the mainstay of treatment for patients with botulism and has significantly reduced the mortality rate over the past 40 years.^3,6,8,20 Death is commonly associated with airway obstruction and respiratory muscle paralysis.

Any patient with a suspected case of botulism should be admitted to an ICU immediately.^12,19 Supportive therapy with mechanical ventilation should be initiated at the earliest signs of respiratory decompensation. Gastric lavage should be attempted if recent food exposure is suspected. The primary concern in a newly diagnosed case of foodborne botulism is to utilize cathartic agents or enemas to remove any unabsorbed toxin. Cathartic agents containing magnesium should be avoided to reduce the potential enhancement of the botulinum toxin that has been reported with elevated magnesium levels.^3,19 When wound botulism is suspected, surgical debridement should be performed, followed by appropriate antimicrobial treatment.³ Antibiotic therapy has not been proved valuable in the treatment of botulism.²¹

Antitoxin administration The pharmacologic treatment of choice in foodborne botulism is available through state health departments or the CDC.^22,23 The antitoxin is an equine product with antibodies to toxin types A, B, and E. Administration of this antitoxin neutralizes toxin molecules before they are bound to nerve endings. The equine antitoxin may stabilize any deficit, although it will not reverse the paralysis.²⁴ The antitoxin is administered IM. Patients may be screened for hypersensitivity with a small challenge dose of the antitoxin before completing the full dosage. Before the antitoxin is administered, diphenhydramine and epinephrine should be available for rapid administration.^1,3,18,24

Infant botulism antitoxin Human-derived antitoxin, called Botulism Immune Globulin Intravenous (Human) (BIG-IV), may be used in the treatment of infant botulism; it may reduce the need for mechanical intervention and tube feeding. The FDA licensed this product as BabyBIG in 2003, and the California Department of Health Services has it available.^11,24,25 When administered early in the illness, usually less than 3 days after the initial hospitalization, the human antitoxin has been shown to be effective in reducing hospital stay and severity of illness in infants younger than 1 year.²⁶

Inhalation vaccine Investigation is ongoing into the development of an inhalation vaccine against botulinum toxin, and the initial reports are promising.^27,28 The research is continuing, and inhalation vaccines may be available in the future.²⁷

Conclusion

A suspected outbreak of C botulinum infection could constitute a medical and public health emergency that would require immediate government intervention. Early recognition and rapid supportive therapy of patients with suspected botulism are essential. Mechanical ventilation is recommended when the patient’s vital capacity falls below 15 mL/kg or when negative inspiratory force measures less than 20 cm of water.¹⁸ Passive administration of the trivalent equine antitoxin may stabilize the patient, but it will not reverse existing paralysis. In patients who survive the initial infection, recovery may be prolonged, occurring over the course of 1 year as new synaptic terminals are developed.¹⁸

REFERENCES

28. Simpson LL. Identification of the major steps in botulinum toxin action. Annu Rev Pharmacol Toxicol. 2004;44:167-193.

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