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BOTULISM
TOXICOLOGY, CLINICAL PRESENTATION AND MANAGEMENT

 

PigAgent: Botulinum toxin derived from Clostridium botulinum

Common name: "Sausage Poison"

History
Potentials as a biological weapon
Toxicology and Microbiology
Epidemiology
Transmission
Incubation Period
Clinical Features
Morbidity / Mortality
Diagnosis
Features of an outbreak suggesting deliberate release of botulinum toxin
Therapy
Prevention
Reporting/ Appropriate action
Selected References
View Dr. Janak Koirala's Presentation on Botulism (Adobe Acrobat Reader required)

History

  • Justinus Kerner (1786-1862) published first complete description as a fatty poison. He also performed animal and clinical experiments, and even thought about its therapeutic usage. He is also known as "Sausage Kerner" in Germany as the toxin was known as "sausage poison" at that time. [1]
  • Muller (Germany, 1870) further characterized and named it "botulus", which means "sausage" in Latin. Van Ermengem (Belgium, 1895) discovered the bacteria. Alan B. Scott (USA) used it for chemodenervation in monkey (1973) and human (1980).

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Potentials as a biological weapon

  • Japanese fed their prisoners C. botulinum cultures in 1930's with fatal effects.
  • Allied troops received botulinum toxoid vaccine during world war II with the concerns that Germany had weaponized botulinum toxin. [5]
  • Besides USA and former USSR, four other countries have developed or are believed to be developing botulinum toxin as biological warfare agent- Iraq, North Korea, Iran and Syria.
  • A Japanese cult Aum Shinrikyo dispersed aerosols in Tokyo and US military installations in Japan on 3 occasions between 1990-95. [3]
  • United Nations inspecting team visiting Iraq after Gulf War (1991) reported that Iraq admitted to having 19000 L of concentrated botulinum toxin, enough to kill the entire human population 3 times by inhalation. In 1990 Iraq deployed 600-km range missiles and 100 lb bombs filled with botulinum toxin, aflatoxin and anthrax spores. [3]
  • Botulinum toxin may be used to immobilize the opponent in military. It has been estimated that as a point source aerosol, it can be used against a civilian population in a densely populated area to incapacitate or kill 10% of population within 0.5 km downwind. In addition, it can be used to deliberately contaminate food. [3]

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Toxicology and Microbiology

  • Botulinum toxin is an enzyme produced by the Clostridium botulinum, which is a spore forming, obligate anaerobic bacillus. There are 4 genetically diverse groups of this organism. They are commonly found in soils and aquatic habitats throughout the world.
  • Besides, Clostridium baratii and Clostridium butyricum can also produce botulinum toxin.
  • C. botulinum is a anaerobic, motile, gram-positive (in young cultures), straight to slightly curved rod with oval, subterminal spores. It is about 0.5-2.0 µm in width, 1.6-22.0 µm in length.
  • Botulinum toxin is the most poisonous substance known to human. One gram of crystalline toxin is enough to kill one million people. There are 7 subtypes of this toxin, designated with letters A through G. LD50 (lethal dose to 50% of exposed population) for botulinum toxin is estimated to be 1ng/kg parenterally and 3ng/kg by inhalational route. [5]
  • It is a zinc protease that cleaves fusion proteins, which are needed at neuronal vesicles to release acetylcholine into the neuromuscular junction. This blockade results in flaccid paralysis of muscles.
  • Therapeutic use of botulinum toxin: US FDA has approved botulinum toxin preparations (type A= BOTOX, type B= Myobloc) for the treatment of cervical dystonia, blepharospasm, glabellar lines, spasmodic torticollis, strabismus. BOTOX has also been approved for the treatment of glabellar frown lines in both USA and Canada. [2,14]

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Epidemiology

  • Worldwide distribution: sporadic cases, family and general outbreaks occur where food products are prepared or preserved by proper methods
  • USA (source: CDC, year 1999): 174 cases of botulism reported, 26 foodborne, 107 infant botulism, and 41 wound botulism.
  • Recently identified vehicles for foodborne botulism: homemade salsa, baked potatoes sealed in aluminium foil, cheese sauce, sauteed onions under a layer of butter, garlic in oil, salted or fermented fish, Jalapeno peppers, potato salad, etc. [18]

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Transmission

  • 3 natural forms: foodborne, wound, intestinal- bacteria multiply in food or necrotic tissues of wound or intestines, resulting in toxin production.
  • Inhalational: manmade aerosolized form can be used as weapon of bioterrorism.

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Incubation Period

  • Foodborne: typical: 12-72 hrs (range: 2 hrs to 8 days)
  • Inhalational: approximately 72 hrs

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Clinical Features

  • Classic triad of botulism:
    1. acute, symmetric, descending flaccid paralysis with prominent bulbar palsies
    2. no fever
    3. clear sensorium
  • Features of bulbar palsy present in >90% patients: diplopia , dysarthria, dysphonia, dysphagia (difficulty with seeing, speaking and swallowing)
  • Blurry vision with ptosis, diplopia, enlarged pupils with sluggish reactions
  • Flaccid paralysis progresses in descending manner- loss of head control, generalized weakness and hypotonia, loss of deep tendon reflexes (in days), airway obstruction and respiratory muscle paralysis requiring ventilatory support
  • Death results from airway obstruction and respiratory muscle paralysis
  • Gastrointestinal symptoms present in foodborne botulism- abdominal cramps, nausea, vomiting, diarrhea
  • Excerpts from Justinus Kerner's monograph:
    Symptoms of Sausage Poisoning (Botulism):
    "The tear fluid disappears, the gullet becomes a dead and motionless tube; in all mucous cavities of the human machine the secretion of the normal mucus stands still, from the biggest, the stomach, towards the tear canal and the excretory ducts of the lingual glands. No saliva is secreted. No drop of wetness is felt in the mouth, no tear is secreted anymore. No earwax appears in the auditory canal, also signs of drying out of the Eustachian tube become apparent. No mucus is secreted in the nose; no more sperma is secreted, the testicles decrease. Urination can only be performed by standing and with difficulty. Extreme drying out of the palms, the soles and the eyelids occurs."

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Morbidity / Mortality

  • Paralysis may persist for weeks to months
  • Mortality: food botulism- 5-10% treated, 60% untreated patients - Early deaths: result from a failure to recognize the severity of disease or from secondary pulmonary or systemic infections - Deaths after 2 weeks: usually from the complications of long-term mechanical respiratory management.

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Diagnosis

  • based on clinical features for initial management
  • EMG (electromyography) may helpful in establishing diagnosis:
    • normal NCV (nerve conduction velocity) and sensory nerve function
    • a pattern of brief small amplitude motor potentials
    • a repetitive nerve stimulation at 20-50 Hz may show a characteristic incremental response.
  • Laboratory diagnosis: Botulinum toxin is identified by mouse bioassay, which can detect as little as 0.03ng of the toxin.
    • Botulinum toxin assay is available in CDC and state labs
    • samples of serum, gastrointestinal content and suspected source (e.g. food) should be collected and tested for botulinum toxin
    • Fecal and gastric samples can also be cultured anaerobically. Takes 7-10 days (range 5-20 days).
    • Acceptable specimens (for testing at higher-level LRN laboratories) [4]:
      • Clinical specimens: gastric contents, exudates, tissues, serum, etc.
      • Postmortem specimens
      • Culture/isolate
      • Food samples (solid or liquid)
      • Environmental samples: soil, water
    • Precautions [4]:
      • These procedures should be performed in microbiology laboratories that use Biological Safety Level-2 practices.
      • Level A Laboratories should not attempt to culture, identify the organism, or attempt to perform toxin analysis.
  • Enzyme linked immunosorbent assay from nasal mucosa taken within 24 hours of exposure has been used by military for detection of aerosolized toxin [5]. Alternative in vitro assays, amplified ELISA and PCR are under development [9,10,16].
  • CSF remains normal but may be useful to differentiate from other CNS causes.

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Features of an outbreak suggesting deliberate release of botulinum toxin

  • Outbreak of a large number of cases of acute flaccid paralysis with prominent bulbar palsies
  • Outbreak with an unusual botulinum toxin type (i.e., type C, D, F, or G, or type E toxin not acquired from an aquatic food)
  • Outbreak with a common geographic factor among cases but without a common dietary exposure, i.e. suggesting a possible aerosol attack.
  • Multiple simultaneous outbreaks with no common source A careful travel and activity history, as well as dietary history, should be taken in any suspected botulism outbreak. Patients should also be asked if they know of other persons with similar symptoms.

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Therapy

  • Passive immunization:
    • Botulinum antitoxin is an equine antitoxin available from CDC via state and local health departments in USA. It contains neutralizing antibodies against A, B and E.
    • A heptavalent (A-G) investigational antitoxin is held by US Army.
    • A human antitoxin (Human Botulism Immune Globulin, HBIG) is available as an investigational agent for infant botulism (California Department of Public Health) [15]
    • Each 10ml vial of trivalent equine antitoxin (ABE) contains 5500-8500 IU of antibodies of each type, and is administered IV after diluting 1:10 with 0.9% saline.
    • Administer as soon as possible after clinical diagnosis to minimize neurological progression. It does not reverse existent paralysis.
    • One vial of antitoxin is generally enough for food borne botulism.
    • In case of intentional exposure, adequacy can be confirmed by retesting serum for toxin after administering usual dose of antitoxin.
    • Children, pregnant women and immunocompromized group have been treated with equine antitoxin safely.
    • Side effects: serum sickness (2%), urticaria (9%), mild hypersensitivity (18%), anaphylaxis (2%). Skin test followed by desensitization in patients with wheal and flare should be done by administering incremental doses over 3-4 hours. [3]
  • Supportive care
    • reverse trendelenberg positioning (20-250) for airway protection and improved respiration
    • assisted ventilation required in 20% adults and 60% infant botulism
    • fluid and nutritional support
    • treatment of complications including secondary infections
  • Role of antibiotics in treatment of botulism remains unclear, but penicillin G has been recommended to treat wound botulism. Antibiotics are also useful in treatment of secondary infections. Aminoglycosides and clindamycin are contraindicated because of their ability to exacerbate neuromuscular blockade. [3,7,8]

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Prevention

  • Botulinum toxoid
    • a pentavalent (ABCDE), investigational vaccine is available for high risk laboratory personnel and military. Its efficacy tested during Gulf war showed good immunogenic response with a second booster (28% with first, 97% with booster). [12]
    • A tetravalent vaccine (ABEF) tested in Japan seems to need 3 or more doses [13]. A candidate vaccine against botulinum neurotoxin serotype A (BoNT/A) developed by using Venezuelan equine encephalitis (VEE) virus vector is also being tested [17]
  • Postexposure prophylaxis
    • Early treatment with antitoxin after exposure to botulinum toxin has been shown to reduce neurological manifestations.
    • To balance between the need of scarce equine antitoxin with its potential side effects and the advantages of early treatment after an intentional or unintentional outbreak, it has been suggested to closely observe exposed patients and administer antitoxin when early signs appear.
    • CDC maintains US Botulism Surveillance System and releases antitoxin through its network within United States. CDC also provides antitoxin to other countries of Western Hemisphere through its contract with PAHO (Pan American Health Organization) with exception of Canada. Canada has its own supply of botulinum antitoxin. [11]
  • Decontamination:
    • Botulinum toxin can be destroyed by heating food and drink to core temperature of 850 C for 5 minutes, but all suspected food should be removed and sent to Public Health Department for testing.
    • wash exposed clothes and skin with soap and water
    • clean objects and surfaces with 0.1% hypochlorite bleach solution
    • covering mouth and nose with clothing provides some protection from aerosolized toxin
  • Infection Control: standard precautions only

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Reporting/ Appropriate action

Clinicians:
Following steps are recommended by the Working Group on Civilian Biodefense [3]:

Clinicians Caring for Patients With Suspected Botulism Should Immediately Contact Their:

  1. Hospital epidemiologist or infection control practitioner, and
  2. Local and state health departments If the local and state health departments are unavailable, contact the CDC: (404) 639-2206; (404) 639-2888

Labs:
Following Lab Protocol has been recommended by CDC, ASM and APHL [4]:

  1. Consult with state public health laboratory director (or designate) if C. botulinum toxin is suspected.
  2. General instruction and information:
    1. Preserve original specimens pursuant to a potential criminal investigation and possible transfer to an appropriate LRN laboratory as instructed.
    2. Environmental/nonclinical samples and samples from announced events should not be received by a Level A laboratory; submitter should contact the state public health laboratory directly.
    3. The state public health laboratory/state public health department will coordinate notification of local FBI agents as appropriate.
    4. Assist local law enforcement efforts in conjunction with guidance received from the state public health laboratory.
    5. FBI and state public health laboratory/state public health department will coordinate the transfer of isolates/specimens to a higher level LRN laboratory as appropriate.
  3. In conjunction with state public health laboratory, the laboratory may contact CDC as appropriate.
    1. Emergency number, 24 h a day, 7 days a week: 770-488-7100
    2. National Botulism Surveillance and Reference Laboratory: 404-639-3867

     

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Selected References

  1. Ergbuth FJ, Naumann M. Historical aspects of Botulinum toxin: Justinus Kerner (1786-1862) and "Sausage Poison". Neurology 1999;53:1850-1853.
  2. Carruthers A, Carruthers J. Update on the botulinum neurotoxins. Skin Therapy Lett. 2001 Dec;6(13):1-2.
  3. Arnon SS, et al. Botulinum toxin as a biological weapon: Medical and public health management. JAMA 2001;285:1059-1070.
  4. CDC, ASM, APHL. Basic Protocols for Level A Laboratories for Botulinum Toxin. Dec 2001; 1-13.
  5. Middlebrook JL, Franz DR. Botulinum Toxins. In Textbook of Military Medicine Medical Aspects of Chemical and Biological Warfare; By: The Surgeon General, 1997.
  6. Miller JM. Agents of Bioterrorism. Infect Dis Clin North Am 2001;15(4):1127-1156.
  7. Santos JI, Swensen P, Glasgow LA. Potentiation of Clostridium botulinum toxin by aminoglycoside antibiotics: clinical and laboratory observations. Pediatrics. 1981;68:50-54.
  8. Schulze J, Toepfer M, Schroff KC, et al. Clindamycin and nicotinic neuromuscular transmission. Lancet 1999;354:1792-1793.
  9. Centers for Disease Control and Prevention. Botulism in the United States 1899-1996: Handbook for Epidemiologists, Clinicians, and Laboratory Workers. Atlanta, Ga: Centers for Disease Control and Pre-vention; 1998. Available at: http://www.cdc.gov
  10. Franciosa G, Ferreira JL, Hatheway CL. Detection of type A, B, and E botulism neurotoxin genes in Clostridium botulinum and other Clostridium species by PCR: evidence of unexpressed type B toxin genes in type A toxigenic organisms. J Clin Microbiol. 1994;32:1911-1917.
  11. Shapiro RL, Hatheway C, Becher J, Swerdlow DL. Botulism surveillance and emergency response: a public health strategy for a global challenge. JAMA. 1997; 278:433-435.
  12. Pittman PR, Hack D, et al. Antibody response to a delayed booster dose of anthrax vaccine and botulinum toxoid. Vaccine 2002;20(16):2107-15.
  13. Torii Y, Tokumaru Y, et al. Production and immunogenic efficacy of botulinum tetravalent (A,B,E,F) toxoid. Vaccine 2002.20(19-20):2556-61.
  14. National Drug Data File (NDDF) from First Data Bank, available on /www.medscape.com/; accessed on 8/12/2002.
  15. Shen WP, Felsing N, Lang D, Goodman G, Cairo MS. Development of infant botulism in a 3-year-old female with neuroblastoma following autologous bone marrow transplantation: potential use of human botulism immune globulin. Bone Marrow Transplant 1994 Mar;13(3):345-7
  16. Ferreira JL, Eliasberg SJ, et al. Detection of preformed type A botulinum toxin in hash brown potatoes by using the mouse bioassay and modified ELISA test. J AOAC Int 2001;84(5)1460-64.
  17. Lee JS, Pushko P, et al. Candidate vaccine against botulinum neurotoxin serotype A derived from a Venezuelan equine encephalitis virus vector system. Infect Immun 2001;69(9):5709-15.
  18. Shapiro RL, Hatheway C, Swerdlow DL. Botulism in the United States: A clinical and epidemiological review. Ann Intern Med 1998;129:221-228.

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