Botulinum toxin

Background and potential as a bioweapon

Botulinum toxin is a CDC Category A Bioterrorism Agent due to its extreme lethality, its ease of production and transport, and the need for prolonged intensive care among survivors. Botulinum toxin is the most poisonous substance known to man. A single gram of crystalline botulinum toxin, evenly dispersed and inhaled, could kill more than 1 million people (Dhaked 2010).

There have been several attempts by terrorists to use botulinum toxin as a bioweapon. Botulinum aerosols were dispersed at multiple sites in Japan, including the Yokosuka U.S. Navy base, on at least three occasions between 1990 and 1995, by the Japanese cult Aum Shinrikyo (Cenciarelli 2019). Fortunately, the attacks failed due to inadequate microbiological techniques, deficient aerosolized generating equipment, or internal sabotage. The cult members obtained their botulism spores from soil collected in northern Japan.

At least four countries listed by the U.S. government as state sponsors of terrorism – Iran, Iraq, North Korea, and Syria, have developed, or are believed to be developing, botulinum toxin as a weapon. After the 1991 Persian Gulf War, Iraq admitted to the United Nations inspection team that they produced 19,000 liters of concentrated botulinum toxin, of which approximately 10,000 liters were loaded onto military weapons. These 19,000 liters of concentrated toxin are not fully accounted for and constitute approximately three times the amount needed to kill the current human population by inhalation.

Pathogenic agents

Botulinum toxin is a potent neurotoxin produced by Clostridium botulinum and sometimes Clostridium butyricum, and Clostridium baratii and Clostridium argentinense. These four species of rod-shaped, anaerobic, spore-forming bacilli commonly occur in soil, sewage, marine sediments, animal and plant products, the intestinal tract, and in wounds of man and animals. Clostridium spores are highly resistant to inactivation, and they can survive for many years in the environment until favorable conditions allow them to germinate, grow, and produce botulinum toxin.

There are currently 7 recognized types of botulinum neurotoxins, A through G. Knowing the toxin type is important to treatment because each toxin type requires a specific antiserum (Botulism - CFSPH. 2018). Human botulism is caused primarily by strains of C. botulinum that produce toxin types A, B, and E (Poulain & Popoff 2019).

Botulinum toxins are easily inactivated by exposure to a few hours of sunlight, 0.1% sodium hypochlorite or 0.1 N NaOH, or by heating to 80°C (176°F) for 20 minutes or > 85°C (185°F) for at least 5 minutes. Their heat resistance varies with composition of the food or other medium, and the concentration of the toxin. Reports suggest that High Temperature Short Time (HTST) pasteurization (72°C/162°F for 15 seconds) is likely to inactivate most or all of the toxin in contaminated milk, while conventional pasteurization at 63°C/145°F for 30 minutes seems to be less effective. Chlorine and other agents can destroy botulinum toxins in water (Botulism 2018).

Click to open Amarra Youtube video of botulinum toxin.

Mode of action

Botulinum toxin blocks the transmission of acetylcholine across the neuromuscular junction between nerves and muscles , producing muscle paralysis, including paralysis of respiratory muscles.

Clinical Course

The five main kinds of botulism are:

Infant botulism can happen if the spores of the bacteria get into an infant’s intestines. The spores grow and produce the toxin which causes illness. The picture shows a six-month-old suffering extreme flaccid paralysis produced by botulinum toxin. Note the lack of muscle tone, especially at the neck.
Wound botulism can happen if the spores of the bacteria get into a wound and make a toxin. People who inject drugs have a greater chance of getting wound botulism. Wound botulism has also occurred in people after a traumatic injury, such as a motorcycle accident or surgery.
Foodborne botulism can happen by eating foods contaminated with botulinum toxin. Common sources of foodborne botulism are homemade foods that have been improperly canned, preserved, or fermented. Though uncommon, store-bought foods also can be contaminated with botulinum toxin.
Iatrogenic botulism can happen if too much botulinum toxin is injected for cosmetic reasons, such as wrinkles, or medical reasons, such as migraine headaches.
Adult intestinal toxemia (also known as adult intestinal colonization) botulism is a very rare kind of botulism that can happen if the spores of the bacteria get into an adult’s intestines, grow, and produce the toxin (similar to infant botulism). Although we don’t know why people get this kind of botulism, people who have serious health conditions that affect the gut may be more likely to get sick.

Symptoms

Botulism typically produces a distinctive syndrome of cranial nerve palsies that can be followed by bilateral, symmetric, descending flaccid paralysis, affecting proximal before distal limb musculature, that might progress to respiratory failure and death. (Rao et al. 2021) The rapidity of onset and severity of botulism depend on the rate and amount of toxin absorption into the circulation

Botulism toxin is a large protein that cannot directly pass through the blood-brain barrier. Patients with botulism are alert and oriented, although ptosis, ocular muscle paralysis, voice changes from vocal cord paralysis, and gait disturbance from skeletal muscle paralysis can be mistaken as manifestations of drug or alcohol intoxication or mental status changes of another origin.

Signs and symptoms of botulism evolve over a period of hours to a few days. The most commonly reported symptoms among patients with botulism were dysphagia, blurred vision; slurred speech, difficulty speaking, and hoarse voice; gastrointestinal symptoms, dry mouth; shortness of breath; and diplopia. The most common signs were descending paralysis, ptosis, and ophthalmoplegia (Rao et al., 2021). Foodborne botulism patients experience symptoms between 12 and 72 hours after the contaminated meal.

Recommendations

Consider botulism when myasthenia gravis or GuillainBarré syndrome are suspected and in a patient with unexplained symmetric cranial nerve palsies, with or without paresis of other muscles.
Conduct thorough, serial neurologic examinations to detect the neurologic deficits of botulism and their progression.
If botulism is suspected, immediately contact the local or state health department’s emergency on-call staff to arrange an emergency expert clinical consultation and, when indicated, request botulinum antitoxin from CDC (Rao et al. 2021).

INSTANT FEEDBACK:

The first symptom of botulism is respiratory distress.

Botulism is often misdiagnosed as Gullain-Barre syndrome, stroke, or myasthenia gravis. Botulism differs from other conditions causing flaccid paralysis in that its primary effects are:

weakness and paralysis of the cranial nerves compared to milder muscle weakness below the neck,
in its symmetry, and
in its absence of sensory nerve damage.

Diagnostic confirmation of botulism is by specialized laboratory testing that often takes days to complete. Routine lab tests are usually unremarkable. Therefore, clinical diagnosis is the foundation for early recognition of and response to a bioterrorist attack with botulinum toxin. Botulism and botulinum toxin are not contagious and cannot be transmitted from person to person.

INSTANT FEEDBACK:

Treatment for botulism should be delayed until laboratory tests confirm the diagnosis.

Disease Management

Therapy for botulism consists of supportive care and passive immunization with botulism antitoxin. Antibiotics do not affect botulinum toxins. Administration of antitoxin can minimize subsequent nerve damage and the severity of the disease but does not reverse already existing paralysis. The use of botulism antitoxin for post-exposure prophylaxis is limited by its scarcity and potential complications. There are also few published data on the safety of botulism antitoxin. Due to the potential risks of equine antitoxin therapy, it is less sure how to best care for persons exposed to botulinum toxin but not yet ill. Infants should not be treated with botulism antitoxin (CIDRAP News, 2019).

Botulism patients require supportive care that includes feeding by enteral tube or parenteral nutrition, intensive care, mechanical ventilation, and treatment of secondary infections. Patients with suspected botulism should be carefully monitored for impending respiratory failure. Botulism patients should be assessed for their ability to gag and cough, ability to control oropharyngeal secretions, and indicators of respiratory function such as oxygen saturation, vital capacity, and inspiratory force. The proportion of patients with botulism who require mechanical ventilation ranges from 20% to 60%.

A reverse Trendelenburg position may postpone or avoid the need for mechanical ventilation in mildly affected patients because of improved respiratory mechanics and airway protection. With this position, the patient is placed on a flat mattress tilted at 20 degrees. A tightly rolled cloth can be used to support the cervical vertebrae, and bumpers can be used at the foot of the bed to prevent the patient from sliding downward. For those patients who survive, eventual recovery from botulism results from new motor axon twigs that sprout to reinnervate paralyzed muscle fibers, a process that may take weeks or months to complete. In a large outbreak of botulism affecting a major metropolitan area, the need for mechanical ventilators, critical care beds, and skilled personnel might quickly exceed local capacity and persist for weeks or months.

INSTANT FEEDBACK:

A reverse Trendelenburg position may delay the need for mechanical ventilation in a patient with botulism.

Recognition of a covert intentional release of finely aerosolized botulinum toxin would probably occur too late to prevent additional exposures. Covering the mouth and nose with clothing such as a handkerchief, scarf, or shirt may provide some protection when exposure is anticipated. Features of an outbreak that would suggest a deliberate release of botulinum toxin include:

An outbreak of a large number of cases of acute flaccid paralysis with prominent bulbar palsies.
An outbreak with an unusual botulinum toxin type.
An outbreak with a common geographic factor among cases (e.g., air travel, work location), but without a common dietary exposure.
Multiple simultaneous outbreaks with no common source.

Medical uses

U.S. Approval for BOTOX® (onabotulinumtoxinA) was granted in 1989, for intramuscular injection to treat muscle spasticity , intradetrusor, or intradermal use Initial for injection. Small doses of purified botulinum toxin are injected into muscles to block the release of acetylcholine from motor neurons, thereby preventing muscle spasticity, according to the FDA. The toxin thus weakens or paralyzes the injected muscle (FDA 1989).

Other uses include: overactive bladder, urinary incontinence, chronic migraine, strabismus, spasticity.

References:

Botulism (2018). The Center For Food Security and Public Health (CFSPH). Retrieved September 6, 2022, from https://www.cfsph.iastate.edu/Factsheets/pdfs/botulism.pdf

Cenciarelli, O., Riley, P. W., & Baka, A. (2019). Biosecurity Threat Posed by Botulinum Toxin. Toxins, 11(12), 681. https://doi.org/10.3390/toxins11120681

Dhaked, R. K., Singh, M. K., Singh, P., & Gupta, P. (2010). Botulinum toxin: bioweapon & magic drug. The Indian journal of medical research, 132(5), 489–503.

Poulain, B., & Popoff, M. R. (2019). Why Are Botulinum Neurotoxin-Producing Bacteria So Diverse and Botulinum Neurotoxins So Toxic?. Toxins, 11(1), 34. https://doi.org/10.3390/toxins11010034

Rao, A. K., Sobel, J., Chatham-Stephens, K., & Luquez, C. (2021). Clinical Guidelines for Diagnosis and Treatment of Botulism, 2021. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports, 70(2), 1–30. https://doi.org/10.15585/mmwr.rr7002a1

CIDRAP News. (2019). Botulism. CIDRAP. Retrieved September 6, 2022, from https://www.cidrap.umn.edu/infectious-disease-topics/botulism#overview&1-8

US Food and Drug Administration Botox Label (1989). Retrieved 8/15/2022, from https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103000s5232lbl.pdf

US WorldMeds - Mechanism of Action (2009). Amerra Medical. Youtube video https://youtu.be/R-A8YI7Ik4g?t=1