Botulism

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148 Botulism

Botulism is the neuroparalytic disorder resulting from intoxication with exotoxins produced by Clostridium botulinum and several other strains of clostridia. C. botulinum are spore-forming obligate anaerobic bacilli ¹ whose heat-resistant spores are widely distributed in soil and marine sediment throughout the world.² The term botulism is derived from the Latin word for “sausage,” botulus. Botulism initially was recognized as sausage poisoning in Europe in the early 19th century. Kerner, a German health official, characterized the relationship between sausage ingestion and paralysis in 230 people in 1820.³ The toxin and the bacterium were initially demonstrated by Van Ermengem⁴ in his study of an epidemic of foodborne botulism following raw ham consumption at a Belgian funeral music festival in 1895. In addition to foodborne botulism after ingestion of preformed toxin, forms of botulism owing to in vivo toxin production subsequently were recognized, including wound botulism in 1943,⁵ infant botulism in 1976,^6,⁷ and adult intestinal botulism in 1986.⁸ Inhalational botulism has been identified only in a single outbreak in humans⁹ but has received more recent attention related to the potential for aerosolized toxin used as a biological weapon.¹⁰

Toxin Characteristics

Seven distinct serotypes of botulinum toxin, A through G, are defined by the absence of cross-neutralization with antitoxin.¹¹ Human disease is produced by types A, B, E, and rarely F toxin, whereas types C and D produce disease in birds and mammals.¹² Type G has been implicated in human disease only rarely.^12,¹³ Neurotoxigenic strains of Clostridium baratii may produce type F toxin,^14,¹⁵ and some strains of Clostridium butyricum may produce type E toxin.¹⁶

Botulinum toxins are 150-kD polypeptides that are converted during bacterial lysis by proteases into an active form consisting of a 50-kD light chain and a 100-kD heavy chain joined by a disulfide bond.¹⁷ After absorption into the systemic circulation, the carboxy-terminal domain of the heavy chain facilitates binding of the toxin to polysialoganglioside receptors on neuronal membranes, whereas the amino-terminal domain of the heavy chain mediates translocation of the toxin into motor or autonomic neurons.^18,¹⁹ The light chain is a zinc endopeptidase that cleaves a toxin-specific location of one or more of the SNARE (soluble N-ethylmaleimide-sensitive fusion associated protein receptor) proteins mediating the docking and fusion of acetylcholine vesicles with the presynaptic membrane at the neuromuscular junction, in autonomic ganglia, and in parasympathetic nerve terminals.²⁰ SNARE proteins, SNAP-25 (synaptosomal-associated protein of 25 kD) and syntaxin, are associated with the presynaptic membrane, whereas synaptobrevin or vesicle-associated membrane protein (VAMP) is located on the synaptic vesicle membrane. SNAP-25 is cleaved by types A, C, and E toxins, and syntaxin is cleaved by type C toxin.²¹^–²³ Synaptobrevin is cleaved by types B, D, F, and G and tetanus toxins.²⁴^–²⁶ After cleavage of SNARE proteins by botulinum toxin, the release of acetylcholine is permanently halted at affected synapses. Recovery from botulism occurs when the presynaptic neuron sprouts another nerve terminal to reform the cholinergic synapse.²⁷^–²⁹ The original synapse remains intact, however, and over a period of months becomes functional again. After this occurs, the new synapse is pruned.

Botulinum toxin is considered to be the most toxic substance by weight,³⁰ with a lethal dose in humans estimated to be approximately 1 ng/kg of type A toxin.³¹ By extrapolation from primate studies,³² the lethal dose of type A toxin for a 70-kg man is estimated to be 70 µg by mouth, 0.70 to 0.90 µg by inhalation, and 0.09 to 0.15 µg by intramuscular or intravenous routes.³³ In contrast to the heat-resistant spores of C. botulinum, the toxins are heat labile and are inactivated by heating to 85°C for at least 5 minutes.³⁴

Forms of Human Botulism

Foodborne Botulism

Ingestion of contaminated food, with absorption of toxin from the duodenum and jejunum, causes foodborne botulism. Because several individuals may be exposed to a single contaminated food source, foodborne botulism often presents in outbreaks. The average annual number of foodborne botulism cases in the United States between 1973 and 1998 was 24 (range 14-94),³⁵ with an average of 9.4 outbreaks a year between 1950 and 1996.¹² The most frequently implicated foods include home-canned vegetables, fruits, and fish.¹² Failure to use a proper combination of heat, pressure, and time to kill spores during home canning, particularly with low-acid (pH > 5) foods, may permit survival and germination of spores.³⁶ Although restaurant and commercially prepared foods are responsible for fewer outbreaks (7% from 1950-1996),¹² nearly half of foodborne cases may arise from these sources.³⁷ Fish preparation using fermentation among Alaskan natives is responsible for a large fraction of the total cases (29% from 1973-1998).¹²

Foodborne botulism due to type A toxin is most common in the United States, constituting 45% of outbreaks compared with 36% of outbreaks due to type E and 13% due to type B toxin during the period 1990 to 1996. Type F foodborne outbreaks are rare in the United States.¹² The geographic distribution of foodborne botulism outbreaks mirrors the type of spores residing in soil. Type A spores predominate in the western United States, and type B spores predominate in the northeastern and central United States.^38,³⁹ Type E spores are found in marine life and sediments.^40,⁴¹ In a corresponding fashion, during the period 1950 to 1996, 86% of the type A outbreaks occurred west of the Mississippi River, whereas 61% of the type B outbreaks were from eastern states. Marine products have been implicated in 91% of type E outbreaks.¹²

Signs and symptoms of foodborne botulism generally develop within 12 to 36 hours of ingestion of contaminated food, with the acuity and severity of illness related to the amount of toxin absorbed. In general, a symmetrical, descending paralysis with multiple cranial neuropathies evolves rapidly in the absence of fever or altered sensorium. In foodborne botulism, initial symptoms are often gastrointestinal (GI) and include nausea, vomiting, diarrhea, and abdominal cramping, which may be due to ingestion of other bacterial metabolites along with botulinum toxin in contaminated food.⁴² Parasympathetic dysfunction may present early with dry mouth and blurred vision associated with dilated, poorly reactive pupils. Diplopia often develops secondary to extraocular muscle weakness with paretic, disconjugate eye movements. With paralysis of bulbar muscles, patients may exhibit flaccid dysarthria, chewing difficulty, and dysphagia. The upper extremities, trunk, and lower extremities may become paretic in a descending fashion. Autonomic dysfunction may manifest as GI dysmotility, orthostatic hypotension, altered resting pulse, urinary retention, or hypothermia.⁴³

Respiratory compromise may occur secondary to a combination of upper airway obstruction from weak oropharyngeal muscles and diaphragmatic weakness. Requirements for mechanical ventilation are more prolonged for patients with type A disease (mean 58 days) compared with patients with type B disease (mean 26 days).⁴⁴ The clinical findings related to intoxication with various types of botulinum toxin are varied (Table 148-1), with type A disease causing more frequent extraocular and bulbar muscle weakness, and type B and E disease causing relatively more pupillary and autonomic dysfunction.⁴⁵^–⁴⁷

TABLE 148-1 Symptoms and Signs in Human Botulism Types A, B, and E

With improvements in respiratory care, the case-fatality rate has diminished from 60% during 1899 to 1949 to 12.5% during 1950 to 1996.¹² The fatality risk for the index case in an outbreak is 25%, with a 4% fatality risk for subsequent cases after recognition of an outbreak.⁴⁸ Because of the potential for exposure of other individuals to a contaminated food source and for additional cases accumulating from previous exposure, every case of suspected foodborne botulism should be reported to local and state public health authorities.

Wound Botulism

Wound botulism results from in vivo toxin production in abscessed and devitalized wounds.⁴⁹ In the event of contamination by spores, these wounds provide an ideal anaerobic environment for spore germination and local colonization by C. botulinum with absorption of toxin into systemic circulation. In contrast to the rapid onset of botulism in foodborne disease with ingestion of preformed toxin, the incubation period for wound botulism is 7 days (range 4-14 days).⁵⁰ Single cases occur in isolation with a case-fatality rate of approximately 15%.⁵¹ Before 1980, wound botulism was a rare disorder generally associated with deep wounds containing avascular areas. Between 1943 and 1985, 33 cases were reported in the United States.¹² During the period 1986 through 1996, 78 cases of wound botulism were reported in the United States, most related to subcutaneous injection or “skin popping” of black tar heroin.^12,⁵² Wound botulism due to sinusitis after repeated cocaine inhalation also has been observed.⁵³ The neurologic signs and symptoms are virtually identical to foodborne disease except for the absence of prodromal GI symptoms.¹² When present, fever is related to the wound infection.⁵⁴ The diagnosis should be suspected in patients with a drug-injection history and without known exposure to a contaminated food source.⁵⁵

Intestinal Botulism

Infant Intestinal Botulism

Infant and adult intestinal botulism result from the ingestion of C. botulinum spores that germinate, colonize the large intestine, and produce botulinum toxin in vivo.⁶ Infant intestinal botulism is now recognized as the most common form of botulism in the United States, with approximately 100 cases reported annually. About half of the cases relate to type A toxin, and the other half to type B intoxication.¹² Most individual cases occur sporadically, although rare unexplained clusters are reported.⁵⁶^–⁵⁸ Since the recognition of infant intestinal botulism in 1976, nearly half of the reported cases have occurred in California. The geographic distribution of infant botulism is unexplained, with the highest incidence rates observed in Delaware, Hawaii, Utah, and California.¹² The average age of onset is 13 weeks, and most cases occur before 6 months, although some cases have occurred at 15 months of age.¹²

Ingestion of ambient C. botulinum spores, distributed widely in soils and dust, is thought to represent the primary route of exposure.⁵⁶ Honey is also a source of spores and has been implicated as a significant risk for infant intestinal botulism.⁵⁹^–⁶¹ In an animal model of infant intestinal botulism, mice between 7 and 13 days old proved susceptible to intestinal colonization with C. botulinum after intragastric injection of spores.⁶² Epidemiologic studies suggest a parallel peak human susceptibility to intestinal colonization by C. botulinum between 2 and 4 months of age.⁶³ This susceptibility appears related to the intestinal flora in the immature infant GI tract. The resident flora are influenced by an infant’s food sources,⁶⁴ although the potential significance of breastfeeding versus formula feeding as a risk for infant intestinal botulism is unresolved.⁶⁵

A clinical spectrum of disease exists, with some infants exhibiting relatively mild and limited disease involving several days of constipation, poor feeding, and lethargy, and other infants developing acute tetraparesis and respiratory failure.⁶⁵ In classic cases, constipation is often the initial symptom, followed by lethargy, poor feeding, and weak cry. Examination reveals hypotonia with head lag, ptosis, reduced facial expression, and reduced gag, suck, and swallow reflexes. Deep tendon reflexes are reduced or absent. Extraocular movements are often paretic, and pupils may be large and poorly reactive. In one series, more than half of the patients were intubated and mechanically ventilated, usually following loss of protective upper airway reflexes.⁶⁶ Although the course is variable, most hospitalized infants reach maximal paralysis at approximately 1 to 2 weeks after hospitalization and begin to improve after 1 to 3 weeks.⁶⁵ In California between 1976 and 1991, the average length of hospitalization was 4.9 weeks. A longer length of stay was documented for type A cases (5.7 weeks) compared with type B cases (3.6 weeks), suggesting that type A intoxication causes more severe disease.⁶⁵ The case-fatality rate is less than 1% in hospitalized patients in the United States.⁵⁶

Adult Intestinal Botulism

Children and adults also may be susceptible to intestinal colonization and in vivo toxin production by C. botulinum, C. baratii, or C. butyricum when the gastric barrier is compromised and the intestinal flora are altered.^8,^15,^67,⁶⁸ Previously classified by the Centers for Disease Control and Prevention (CDC) as “botulism of undetermined origin,” adult intestinal botulism has occurred in the setting of intestinal surgery, gastric achlorhydria, broad-spectrum antibiotic treatment, and inflammatory bowel disease.⁶⁹^–⁷¹ Although adult intestinal botulism is uncommon (10 cases reported between 1986 and 1996),⁷¹ it is probably underdiagnosed.

Inhalational Botulism

Inhalational botulism does not occur in nature but is the result of an attempt to use the toxin in aerosolized form as a bioweapon.¹⁰ The three documented human cases were reported from Germany in 1962, when botulinum toxin type A became accidentally reaerosolized during disposal of laboratory animals.⁹ These patients initially developed dysphagia on day 3 after exposure and exhibited tonic pupils, paretic eye movements, dysarthria, and diffuse weakness by day 4. In animal experiments, monkeys became symptomatic 12 to 18 hours after exposure to aerosolized toxin, with descending paralysis and death in some animals.⁷² Aerosolized botulinum toxin was released by the Japanese religious cult, Aum Shinrikyo, on several occasions in the 1990s in Japan, although the attacks were not known to have produced human illness.¹⁰ By the time of the 1991 Persian Gulf War, the state of Iraq had produced large quantities of concentrated botulinum toxin which were loaded onto weapons for military use but never deployed.⁷³

Release of aerosolized toxin has the potential to produce a botulism outbreak. The features of such an outbreak that might suggest a deliberate release of toxin ¹⁰ include: numerous cases within an outbreak (the mean number of cases in foodborne outbreaks has averaged 2.5 for many years)¹²; toxin types within an outbreak that rarely cause natural disease (type C, D, F, G, or E not related to marine sources); outbreaks with a common geographic factor without a common dietary exposure; and multiple simultaneous outbreaks.⁷⁴

Iatrogenic or Inadvertent Botulism

The therapeutic use of botulinum toxin for dystonia, spasticity, hyperhidrosis, sialorrhea, and other conditions occasionally has resulted in inadvertent paresis of nearby noninjected muscles, such as dysphagia in neck muscle injections for cervical dystonia ⁷⁵ and jaw dislocation after parotid injections for sialorrhea in amyotrophic lateral sclerosis.⁷⁶ Although there are rare reports of paretic muscles distant to the site of injection,^77,⁷⁸ it has been estimated that healthy patients would require a 10-fold toxin overdosing to develop systemic symptoms.⁷⁹ Nevertheless, single-fiber electromyography studies showed abnormal neuromuscular transmission in muscles distant to botulinum toxin injections.⁸⁰^–⁸² Patients with underlying neuromuscular disorders seem to be predisposed to developing generalized weakness after therapeutic intramuscular botulinum toxin injections.⁸³^–⁸⁵ Systemic autonomic dysfunction also has been noted after therapeutic injections of type B toxin.⁸⁶

Diagnosis

The diagnosis of botulism is primarily clinical, with the use of laboratory techniques initially to exclude other diagnoses. Currently the confirmation of a diagnosis of botulism and the identification of the toxin type takes several days. Recommendations for specimen acquisition and diagnostic testing change over time; the most current recommendations are Available at: http://www.bt.cdc.gov/agent/botulism/lab-testing.asp.

Differential Diagnosis

The differential diagnosis for botulism includes Guillain-Barré syndrome and its variants, particularly Miller-Fisher syndrome and polyneuritis cranialis. Classic Guillain-Barré syndrome generally occurs with limb weakness and sensory disturbances and is readily distinguished from botulism. Patients with polyneuritis cranialis who exhibit extraocular and bulbar muscle weakness may be difficult to distinguish clinically from botulism in the early phases of illness. Despite prominent extraocular muscle weakness and areflexia in Miller-Fisher syndrome, the presence of limb ataxia helps to distinguish it from botulism.

Myasthenia gravis also commonly produces weakness of extraocular and bulbar muscles, but the temporal course of the weakness is often fluctuating, with diurnal variation and improvement with rest or acetylcholinesterase medications. In contrast to botulism, myasthenia gravis does not affect autonomic function in general or pupillary function in particular. The presence of acetylcholine receptor antibodies is extremely specific for myasthenia gravis. Lambert-Eaton myasthenic syndrome often is associated with a neuroendocrine carcinoma of the lung and the presence of voltage-gated calcium channel antibodies. Although the symptoms and findings may be similar to botulism, the degree of bulbar paralysis is not as marked, and the clinical course is rarely acute or rapidly progressive.

Tick paralysis produces an acute flaccid paralysis due to neurotoxins of ixodid ticks. A meticulous physical examination of the scalp and intertriginous regions should be performed for an attached tick. Acute brainstem lesions, including strokes, may also be diagnostic considerations, particularly if consciousness is impaired. In suspected infant botulism, the differential diagnosis includes sepsis, meningoencephalitis, Werdnig-Hoffmann disease, congenital myasthenia gravis, and metabolic disorders.

Electrodiagnostic Studies

Electrodiagnostic studies may confirm the presence of a presynaptic neuromuscular junctional disorder and strongly suggest the diagnosis of botulism or may support an alternative diagnosis. In botulism, sensory nerve conduction studies should be normal, and no evidence for segmental demyelination on motor nerve conduction studies (e.g., prolonged F latencies, conduction block, temporal dispersion) should be observed to suggest Guillain-Barré syndrome. Compound muscle action potential amplitudes commonly are reduced in clinically affected muscles.⁸⁷ The more affected muscles are often proximal ones, however, and routine motor nerve conduction studies recorded in intrinsic hand or foot muscles may fail to detect this nonspecific abnormality. In contrast with myasthenia gravis⁸⁸ and Lambert-Eaton myasthenic syndrome,⁸⁹ low-frequency (2-3 Hz) repetitive nerve stimulation studies in botulism rarely show a decremental response in terms of reduced amplitude and area of the compound muscle action potential elicited by stimulating a motor nerve.⁸⁷

The characteristic finding in a presynaptic neuromuscular junctional disorder such as botulism is postexercise facilitation or posttetanic facilitation with high-frequency (20-50 Hz) repetitive nerve stimulation. Although Lambert-Eaton myasthenic syndrome and botulism share this finding, posttetanic facilitation may be less prominent ⁹⁰ and more sustained⁹¹ in botulism. Proximal muscles also may exhibit a comparatively greater degree of facilitation in botulism.⁹⁰ Posttetanic facilitation may be more common in type B botulism compared with type A disease.⁹²

Needle electromyography may reveal low-amplitude, short-duration motor unit potentials with an unstable firing pattern, although this nonspecific finding may be observed in many motor unit disorders.⁹⁰ Positive sharp waves and fibrillation potentials also are observed in about half of cases.⁹³

Single-fiber electromyography uses statistical analysis of muscle fiber action potentials generated by the same motor neuron to evaluate neuromuscular transmission. It is the most sensitive diagnostic test for detecting abnormal neuromuscular transmission, although it cannot distinguish reliably between presynaptic neuromuscular disorders. In botulism, it is more sensitive than repetitive nerve stimulation studies for showing neuromuscular junctional pathology.⁹⁴^–⁹⁶

Mouse Bioassay

Confirmatory testing for botulism currently involves a mouse bioassay, which is available only through the CDC and several state laboratories. In the mouse bioassay, mice are inoculated with type-specific antisera and patient serum or extracts from samples of body fluids or suspicious foodstuffs. In a positive mouse bioassay, all the mice die except those receiving the antisera matching the botulinum toxin type present in the patient or food specimens. Test results are generally available within 1 or 2 days after inoculation.¹⁰ Details regarding specimen preparation and handling are available online.¹² Specimen samples in suspected cases of foodborne botulism should include serum, feces, gastric aspirates, vomitus, and foods suspected to be contaminated. In wound botulism, serum, feces, exudate, débrided tissue, and wound swab samples should be examined. In intestinal botulism, serum and feces should be sampled.¹² To obtain an adequate fecal sample, particularly in infant botulism where constipation is common, an enema using sterile, non-bacteriostatic water may be necessary. In addition to administering extracts to mice, the samples are anaerobically cultured, and the culture isolates are evaluated using the mouse bioassay.

Mass spectroscopy for detection and characterization of botulinum toxins is emerging as a valuable diagnostic technique.⁹⁷ Molecular diagnostic techniques are under development and should eventually replace older techniques.

Management

All cases of suspected botulism should be reported to the hospital epidemiologist or infection control officer and to local or state health departments and the CDC for cases in the United States. This reporting is essential to coordinate laboratory testing and shipment of antitoxin and to initiate investigation of the toxin source.¹⁰ Patients with suspected or confirmed botulism should be monitored carefully in an intensive care unit (ICU), with particular attention to their ability to protect the upper airway. Many patients require intubation and mechanical ventilation. Purgatives or activated charcoal may be useful if there is suspicion of residual contaminated food in the GI tract.⁵⁴ The use of antibiotics that impair neuromuscular transmission should be avoided, particularly aminoglycosides and macrolides.^98,⁹⁹

Botulinum antitoxins may reduce the duration and severity of neurologic dysfunction associated with botulism if administered early in the course of disease. The effect of antitoxin is limited to circulating toxin, and the paralytic effects of previously bound and internalized toxin are not reversed by antitoxin.^48,⁶⁵ Four types of antitoxin currently are available in the United States: (1) a licensed bivalent (A, B) human antiserum for infant botulism, (2) a licensed bivalent (A, B) equine antiserum, (3) an investigational monovalent (E) equine antiserum, and (4) an investigational heptavalent (A, B, C, D, E, F, G) antiserum.¹⁰⁰

Botulism Immune Globulin Intravenous (Human)

Botulism immune globulin intravenous (BIG-IV) is a licensed, bivalent human antiserum (type A, B) available for treatment of infant botulism. A 5-year randomized, double-blinded, placebo-controlled treatment trial demonstrated the safety and efficacy of botulism immune globulin intravenous in infant botulism. The mean length of hospital stay was significantly reduced in patients receiving BIG-IV (from 5.5 weeks to 2.5 weeks).⁶⁵ BIG-IV was officially licensed by the U.S. Food and Drug Administration (FDA) in October 2003 for treatment of infant botulism types A and B under the proprietary name of BabyBIG. BIG-IV is available through the California Department of Health Services (24-hour telephone number: 510-231-7600). Current information on infant botulism treatment is Available at: http://www.infantbotulism.org.

Serotherapy

A heptavalent despeciated equine antitoxin (H-BAT) is available from the U.S. Centers for Disease Control and Prevention, and is essentially devoid of serum sickness risk. H-BAT is available through state health departments; more information is Available at: http://www.cdc.gov/laboratory/drugservice/formulary.html#ia. and through http://www.infantbotulism.org/general/babybig.php.

Pentavalent Toxoid

An investigational pentavalent toxoid (type A, B, C, D, E) for preexposure prophylaxis is available for military personnel and laboratory workers. A primary series of immunizations is given at 0, 2, and 12 weeks, followed by a 1-year booster.^100,¹⁰¹ Because it induces immunity over several months, the toxoid is not appropriate for postexposure prophylaxis.¹⁰

Key Points

1 Botulinum toxins are zinc endopeptidases that cleave specific sites of proteins mediating the release of acetylcholine at the neuromuscular junction in autonomic ganglia and in parasympathetic nerve terminals.

2 Foodborne botulism is caused by the ingestion of preformed toxin from contaminated food sources. Foodborne disease may present in outbreaks involving multiple individuals.

3 Intestinal botulism is caused by ingestion of clostridial spores in susceptible individuals, with colonization of the intestinal tract and in vivo toxin production.

4 Wound botulism is due to clostridial colonization of individuals with devitalized tissues and subsequent in vivo toxin production. Subcutaneous injection of illicit drugs, particularly black tar heroin, is responsible for a recent increase in cases.

5 Inhalational botulism from aerosolized toxin causes a neuroparalytic syndrome indistinguishable from the other forms of human botulism.

6 Outbreaks due to deliberate release of toxin may be characterized by numerous cases, rare toxin types, a common geographic factor without a common dietary exposure, and multiple simultaneous outbreaks.

7 The cardinal clinical features of botulism include a symmetrical descending paralysis and multiple cranial neuropathies evolving rapidly in the absence of fever or altered sensorium. In foodborne disease, initial symptoms may include nausea, vomiting, diarrhea, and abdominal cramping. In infant intestinal botulism, the initial symptom is often constipation.

8 Differential diagnosis of botulism includes Guillain-Barré syndrome and its variants, myasthenia gravis, Lambert-Eaton myasthenic syndrome, tick paralysis, and acute brainstem lesions. For infant intestinal botulism, the differential diagnosis includes sepsis, meningoencephalitis, Werdnig-Hoffmann disease, congenital myasthenia gravis, and metabolic disorders.

9 Electrodiagnostic studies may help to support the diagnosis, although the findings may not be specific. The mouse bioassay is the confirmatory test for botulism.

10 Airway protection and ventilatory support are the main issues for supportive care.

11 Antitoxin may shorten the course of the disease when administered early to bind circulating toxin.

Annotated References

Arnon SS. Infant botulism. In: Feigin RD, Cherry JD, editors. Textbook of pediatric infectious diseases. 5th ed. Philadelphia: Saunders; 2004:1758-1766.

This chapter summarizes the known pathophysiology of infant intestinal botulism and contemporary treatment guidelines.

Arnon SS, Schechter R, Inglesby TV, et al. Botulinum toxin as a biological weapon: medical and public health management. JAMA. 2001;285:1059-1070.

This consensus report by the Working Group on Civilian Biodefense reviews the clinical and laboratory findings, differential diagnosis, and treatment recommendations for the various forms of human botulism. The features of a botulism outbreak suggesting a deliberate release of toxin are highlighted.

Centers for Disease Control and Prevention. Botulism in the United States, 1899-1996: handbook for epidemiologists, clinicians, and laboratory workers. Atlanta: Centers for Disease Control and Prevention; 1998.

Available at: http://www.cdc.gov/ncidod/dbmd/diseaseinfo/botulism.pdf. This comprehensive work provides contemporary epidemiologic information relating to all forms of human botulism and detailed information relating to laboratory confirmation and specimen preparation and handling.

Hughes JM, Blumenthal JR, Merson MH, et al. Clinical features of types A and B foodborne botulism. Ann Intern Med. 1981;95:442-445.

This classic series delineates the clinical symptoms and findings in a large series of patients with the most common toxin types in human foodborne botulism.

References

1 Cato EP, George WL, Finegold SM. Genus Clostridium praemozski 1880, 23AL. In: Smeath PHA, Mair NS, Sharpe ME, Holt JG, editors. Bergey’s Manual of Systematic Bacteriology, vol. 2. Baltimore: Williams & Wilkins; 1986:1141-1200.

2 Hauschild AHW. Clostridium botulinum. In: Doyle MP, editor. Foodborne Bacterial Pathogens. New York: Marcel Dekker; 1989:112-189.

3 Kerner J. Neue Beobachtungen über die in Würtemburg so haüfig vorfallen Vergiftung durch den Genuss gerauchter Würst. Tubingen. 1820. Quoted in Damon SR: Food Infections and Food Intoxications. Baltimore: Williams & Wilkins; 1928. p. 67

4 Van Ermengem E. Üeber einen neuen anaeroben Bacillus und seine Beziehungen zum Botulismus. Z Hyg Infekt. 1897;26:1-56.

5 Davis JB, Mattman LH, Wiley M. Clostridium botulinum in a fatal wound infection. JAMA. 1951;146:646-648.

6 Midura TF, Arnon SS. Identification of Clostridium botulinum and its toxins in feces. Lancet. 1976;2:934-936.

7 Pickett J, Berg B, Chaplin E, et al. Syndrome of botulism in infancy: Clinical and electrophysiologic study. N Engl J Med. 1976;295:770-772.

8 Chia JK, Clark JB, Ryan CA, Pollack M. Botulism in an adult associated with food-borne intestinal infection with Clostridium botulinum. N Engl J Med. 1986;315:239-241.

9 Holzer VE. Botulism from inhalation [in German]. Med Klin. 1962;57:1735-1738.