Bioterrorism Update: Botulinum Toxin

Though it has become an ally of plastic surgeons and other specialists, botulinum toxin is high on the Centers for Disease Control and Prevention's list of potentially deadly foes. In crystalline form, a gram could kill a million people. A neurologist reviews the clinical presentation and management of botulism.

By Coleman O. Martin, MD

In addition to the live agents listed by the Centers for Disease Control and Prevention (CDC) as possible instruments of bioterrorism, several biological products are listed. Among these are botulinum toxin and ricin toxin (from castor beans). Botulinum toxin, which has been used as a therapeutic agent by neurologists, ophthalmologists, plastic surgeons, and ENT surgeons, is considered the most likely of these toxins to have a significant public health impact and is on the CDC's "A" list. Administered by inhalation, a single gram of crystallized toxin would be lethal to more than one million people.

This article reviews the militarization, pathophysiology, and clinical aspects of botulinum toxin.
 

What is botulinum toxin and how does it work?

Botulinum toxin is produced by Clostridium botulinum, a genetically diverse class of anaerobic, spore-forming, gram-positive bacilli. These organisms are ubiquitous in soil and not difficult to isolate. Seven different botulinum toxins have been identified and designated A, B, C, D, E, F, and G. Each of these types is produced by a different strain of the organism. It is not possible to distinguish the type of toxin at clinical presentation.

Once absorbed, all types of botulinum toxin are endocytosed by motor neurons. In presynaptic terminals, the toxins enzymatically cleave proteins that are necessary for exocytosis of acetylcholine. The result is a failure of neuromuscular transmission and flaccid paralysis. Because the toxin is not consumed in the reaction, nanogram quantities can induce months of paralysis.
 

How is botulinum toxin used in clinical practice?

Formulated as the drug Botox, botulinum toxin type A was approved in 1989 for clinical use in a variety of conditions, including strabismus, torticollis, spasmodic dysphonia, and blepharospasm. Once injected into a muscle, it leads to focal weakness within a few days. The benefit persists for approximately three months. With repeated injections, some patients develop type-specific neutralizing antibodies. This was part of the impetus to bring other types of botulinum toxin to the market.

Botulinum toxin type B (Myobloc) was approved in 2000 for spasmodic torticollis and cervical dystonia. Botulinum toxin type F has also been investigated for clinical use but is not approved.
 

Has botulinum toxin been deployed as a biological weapon?

Yes. According to United Nations weapons inspectors, Iraq loaded over 10,000 liters of non-crystalline, concentrated botulinum toxin into specially designed bombs, artillery shells, and SCUD missile warheads prior to the Gulf War. The former Soviet Union also stockpiled botulinum toxin. The Japanese cult Aum Shinrikyo attempted to spread botulinum toxin by aerosol on at least three occasions between 1990 and 1995. Fortunately, these attacks were ineffective due to either technical factors or internal sabotage.
 

What are the routes of exposure to botulinum toxin?

The toxin is absorbed by gastrointestinal mucosa and respiratory epithelium. It does not penetrate intact skin. However, C. botulinum can infect wounds; in fact, 44 cases of wound botulism were reported to the CDC in 1999. Contaminating food and dispersing botulinum toxin as an aerosol are both effective means of inducing botulism.

The stability of botulinum toxin is not equal in all environments. It is most stable in neutral or alkaline foods. Aerosolized botulinum toxin is estimated to degrade at a rate of 1% to 4% per minute. Chlorination and aeration deactivate botulinum toxin, making urban water supplies a poor vector.
 

How does botulism present clinically?

Regardless of the route of exposure, the clinical manifestations of botulism are similar. Onset of symptoms can be as early as six hours after exposure. Cranial nerves show the greatest sensitivity to botulinum toxin. Early signs include ptosis, dilated pupils, dry mouth, diplopia, facial weakness, dysarthria, and aspiration. Facial appearance may lead the clinician to mistakenly conclude that the patient is somnolent.

Botulinum toxin does not cross the blood-brain barrier. The patient's mental status is clear unless ventilation is compromised.

Progression of the disease leads to diffuse weakness and respiratory insufficiency. Gastrointestinal distress associated with foodborne botulism is attributed to bacterial products other than botulinum toxin. Exposure to purified botulinum toxin would likely not produce these symptoms.

What is the differential diagnosis for botulism?

Botulism resembles the uncommon Miller-Fisher variant of Guillain-Barré syndrome. The syndrome causes weakness through demyelination of the peripheral nerves. Like botulism, the Miller-Fisher variant preferentially strikes cranial nerves, but with the additional sign of ataxia.

Other causes of descending paralysis include myasthenia gravis, diphtheria, pontine infarction, tick paralysis, and organophosphate poisoning. Bilateral Bell's palsy causes a similar facial appearance but spares other cranial nerves. Nerve conduction studies and 50-hertz repetitive nerve stimulation can help differentiate botulism from myasthenia gravis and Guillain-Barré syndrome. Patients with diphtheria have an associated fever, sore throat, dysphagia, nausea, vomiting, headache, nasal discharge, and head/neck edema. Pontine infarction has accompanying signs of sensory loss, ataxia, and altered mental status. Paralysis from tick bite is poorly understood but responds to removal of the offending arthropod. Organophosphate poisoning from nerve agents such as sarin cause symptoms of cholinergic toxicity, including salivation, lacrimation, urination, and defecation.

Final confirmation of the diagnosis of botulism is accomplished by sending serum and feces to the CDC for botulinum toxin typing. Though not immediately helpful, typing will indicate whether civilian antitoxin is likely to be effective.
 

Is decontamination necessary?

In suspected aerosol exposures, removal of clothing and washing of the patient are prudent to protect the medical staff. Clothing can be decontaminated by heating to 85° C for five minutes. Treatment of oral exposures with non-magnesium-containing osmotic laxatives may prevent further absorption of the toxin.
 

How is botulism treated?

No therapy is available to reverse paralysis. Equine antitoxin only binds circulating toxin. However, this therapy should be considered for all patients with suspected botulism in an attempt to halt progression of the disease. The CDC maintains stocks of trivalent antitoxin that is active against the most common foodborne and infectious strains (A, B, and E). It is provided in a single 10-ml vial that provides 5500 to 8500 international units of each type-specific antitoxin. The agent is diluted 1:10 in normal saline and administered by slow, intravenous infusion. Urticaria, serum sickness, and anaphylaxis are potential complications.

Measures to screen for allergic reactions are outlined in the product insert. Diphenhydramine and epinephrine should be available to treat hypersensitivity reactions. Botulinum toxin developed specifically for military or terrorist use may contain types C, D, F, or G. The CDC antitoxin would not be effective against these proteins. To combat this, the United States military stocks an investigational heptavalent (A-G) antitoxin. It is unclear whether this medication would be made available in the event of an attack.

Paramount in the treatment of botulism is protection against respiratory failure. In neuromuscular disorders, arterial blood gases and pulse oximetry are insensitive to impending respiratory failure. Repeated bedside spirometry is used to assess diaphragmatic function. Indications for intubation include a vital capacity less than 15 ml/kg or a compromised airway. In a large civilian exposure, a city's hospitals could be overwhelmed with patients requiring respiratory support. The CDC maintains "push-packs" containing respirators in various hospitals around the country. These could be deployed rapidly, allowing units to be converted to temporary pulmonary care units until patients could be redistributed to other municipalities.
 

What is the clinical course of botulism?

Information on the clinical course of botulism is derived from sporadically occurring wound botulism, infantile intestinal botulism, and food poisoning. In patients requiring intubation, respiratory support is needed for two to eight weeks in most cases, although ventilation lasting as long as seven months has been reported. General care requires attention to pressure ulcers, deep venous thrombosis, and depression. Because bowel motility requires cholinergic transmission, constipation is a possible complication.

Recovery from paralysis occurs when motor neurons sprout new synaptic terminals, a process that takes months. In severe cases of botulism, full motor recovery may require more than a year.

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Emerg Med 34(4):58, 2002