Bioterrorism

Botulism

By Jeffrey Duchin, MD
WebMD Scientific American® Medicine

February 2003 -- Botulism is a paralytic illness caused by a potent neurotoxin produced by Clostridium botulinum, an anaerobic, spore-forming bacterium. Natural forms of the disease are foodborne botulism, wound botulism, and infant botulism. Foodborne botulism results from ingestion of improperly processed foodstuffs containing preformed toxin produced by C. botulinum. Wound botulism results from production of botulinum toxin by C. botulinum organisms that contaminate wounds. Infant botulism results from the colonization of the intestinal tract of infants after ingestion of spores. Botulinum toxin has been developed as a biologic weapon. An aerosol attack is considered the most likely use of botulinum toxin for bioterrorism, although intentional contamination of food supplies is possible.29,65 Additional information about the pathogenesis and epidemiology of noninhalational forms of botulism is available elsewhere.

Botulinum toxin is the most potent lethal toxin known. The estimated toxic dose of type A botulinum toxin is 0.001 mg/kg of body weight. There are seven distinct antigenic types of botulinum neurotoxins--types A through G--produced by different strains of C. botulinum. Human botulism is caused primarily by toxin types A, B, and E. Botulinum toxin acts to block neurotransmission by binding irreversibly to the presynaptic nerve terminal at the neuromuscular junction and preventing the release of acetylcholine, resulting in bulbar palsies and skeletal muscle weakness. The toxin is colorless, odorless, and presumably tasteless.29,66,67

Clinical Presentation

The incubation period for foodborne botulism is 2 hours to 8 days; the typical incubation period is 12 to 72 hours. The incubation period for inhalational botulism is not established. Aerosol exposures of monkeys and accidental aerosol exposure of humans have resulted in clinical illness developing 12 to 80 hours after exposure. Type A toxin is associated with more severe disease and a higher fatality rate than type B or E. The neurologic features of all forms of botulism are similar.29,66,67 Although initial symptoms in foodborne botulism may include nausea, vomiting, abdominal cramps, and diarrhea, these symptoms are thought to result from other bacterial metabolites in contaminated food and may not occur in inhalational botulism.

The so-called classic triad of botulism summarizes the clinical presentation: an afebrile patient, symmetrical descending flaccid paralysis with prominent bulbar palsies, and a clear sensorium.66-68 Symptoms of cranial nerve abnormalities nearly always begin in the bulbar musculature; patients typically present with difficulty seeing, speaking, or swallowing. Clinical hallmarks include ptosis, blurred vision, and the so-called four Ds: diplopia, dysarthria, dysphonia, and dysphagia. Cranial nerve abnormalities and bulbar weakness are followed by symmetrical descending weakness and paralysis with progression from the head to the arms, thorax, and legs. The extent of paralysis and rapidity of onset of symptoms are proportional to the dose of toxin absorbed into the circulation. Recovery depends on the regeneration of new motor axon twigs to reinnervate paralyzed muscle fibers; recovery may take weeks to months.

Anticholinergic symptoms are common, including dry mouth, ileus, constipation, nausea and vomiting, urinary retention, and mydriasis. Other symptoms include dizziness and sore throat. Sensory findings are not present, with the exception of circumoral and peripheral paresthesias secondary to hyperventilation resulting from anxiety. Botulinum toxin does not cross the blood-brain barrier. Cranial nerve dysfunction and facial nerve weakness may make communication difficult; these symptoms may be mistaken for lethargy and signs of central nervous system involvement.

Diagnosis

Initiation of treatment with botulinum antitoxin should be based on the clinical diagnosis and should not await laboratory confirmation. A clinician who suspects botulism should immediately contact the local or state health department to facilitate procurement of antitoxin for treatment; arrangements should be made for confirmatory diagnostic testing and initiation of an epidemiologic investigation to identify the source of infection. In cases of potential foodborne botulism, any leftover foodstuffs or containers should be held for testing by the public health laboratory.

Demonstration of botulinum toxin in serum samples by mouse bioassay is diagnostic. Samples of serum (in adults, > 30 ml blood in a tiger-top or red-top tube) obtained before administration of botulinum antitoxin should be submitted for testing. For potential foodborne botulism, samples of stool, gastric aspirate, emesis, and suspect foods should also be submitted.67 The likelihood of finding toxin in the sera of affected patients decreases with time; it is detectable in only 13% to 28% of patients more than 2 days after ingestion.69

The possibility of a bioterrorist attack should be considered in any outbreak of botulism. A bioterrorist attack should especially be considered when a cluster of cases occurs; when an outbreak has a common geographic location but there is no common dietary exposure (suggestive of possible aerosol exposure); when there is an outbreak of an unusual botulinum toxin type; or when multiple simultaneous outbreaks occur. A careful dietary and travel history must be taken to help identify the source. Patients should be asked if they know of others with similar symptoms.

The differential diagnosis of botulism includes stroke and other neuromuscular disorders.66,67 A CT scan of the head may be used to exclude cerebrovascular accident, although it is relatively insensitive in early ischemic stroke [see 11:IV Cerebrovascular Disorders]. Patients with myasthenia gravis will often have characteristic electromyographic findings and serum antibody tests. A test dose of edrophonium (Tensilon) may briefly reverse paralysis in patients with myasthenia gravis but also, reportedly, in some cases of botulism. Guillain-Barr syndrome typically results in ascending paralysis and sensory abnormalities. Cerebrospinal fluid protein is normal in patients with botulism and is normal or elevated in patients with Guillain-Barr syndrome. The rare Miller-Fisher variant of Guillain-Barr syndrome is characterized by descending paralysis and may be confused with botulism. Other conditions that mimic botulism include tick paralysis; poliomyelitis; Eaton-Lambert syndrome; paralytic shellfish poisoning; pufferfish ingestion; and anticholinesterase intoxication with organophosphates, atropine, carbon monoxide, or aminoglycosides.

The electromyogram (EMG) can help distinguish different causes of paralysis. The EMG in botulism demonstrates normal nerve conduction velocity, normal sensory nerve function, and small amplitude motor potentials with facilitation to repetitive stimulation at 50 Hz.70

Treatment

The mainstay of treatment for botulism is supportive care, including intensive care, mechanical ventilation, and parenteral nutrition. Morbidity and mortality are usually from pulmonary aspiration secondary to loss of the gag reflex and dysphagia leading to inability to control secretions, respiratory failure secondary to inadequate tidal volume from diaphragmatic and accessory respiratory muscle paralysis, and airway obstruction from pharyngeal and upper airway muscle paralysis. Careful and frequent monitoring of the gag and cough reflexes, swallowing, oxygen saturation, vital capacity, and inspiratory force are critical. Airway intubation is indicated for inability to control secretions and impending respiratory failure. Secondary infections are common and should be sought in patients who develop fever.

Trivalent (ABE) equine antitoxin is available from the CDC through state and local health departments and should be administered as soon as possible after clinical diagnosis. Antitoxin can prevent progression of disease caused by subsequent binding of toxin but does not reverse the effects of already bound toxin. For this reason, antitoxin is not useful if the patient is no longer showing progression of disease or is improving from maximum paralysis. The amount of neutralizing antibody present in the standard treatment dose of antitoxin far exceeds maximum serum toxin concentrations in foodborne botulism patients, and repeat doses are usually not required. In a biologic attack, however, patients may be exposed to unusually high concentrations of toxin, so serum toxin levels should be assessed after initiation of treatment in such cases to determine the need for repeat doses. Botulism caused by toxin types other than A, B, or E would not respond to the trivalent antitoxin. Limited quantities of an investigational heptavalent (A-G) antitoxin are held by the United States Army. However, because of the time delay involved in typing the toxin, the utility of this product in a biologic attack is probably minimal.66,68

Hypersensitivity reactions, including anaphylaxis, have occurred after administration of botulism antitoxin. For that reason, all patients should undergo a skin test before receiving the antitoxin, and resuscitation equipment should be immediately available. Patients showing a positive hypersensitivity reaction on the skin test can be desensitized over several hours.71,72

Before administering antitoxin, physicians should carefully review the package insert for dosage and adverse effects. Standard regimens can be used in children, pregnant women, and immunocompromised persons with botulism. Botulism immune globulin intravenous is an investigational human-derived neutralizing antibody that is available only for treatment of infant botulism from the California Department of Health Services, Berkeley. The CDC bioterrorism Web site or local public health authorities should be consulted for updated treatment recommendations.29,66,67

Transmissibility and Infection Control

Botulism is an intoxication, not an infection, and thus is not transmitted from person to person. Botulinum toxin does not penetrate intact skin. Standard infection-control precautions are adequate unless meningitis is suspected, in which case droplet precautions are indicated. Clothes of persons exposed to an aerosol release of botulinum toxin should be removed and washed. Exposed persons should shower with soap and hot water. Exposed environmental surfaces can be decontaminated with 0.1% hypochlorite bleach solution.67

References

The author has no commercial relationships with manufacturers of products or providers of services discussed in this subsection.

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