Clostridium botulinum

Background

History

• Named for sausages (botulus) due to a historical association with improperly-cooked sausages

Microbiology

• Large Gram-positive anaerobic bacillus with a subterminal spore
  • Lipase positive and lecithin negative on egg yolk agar
• Diverse species whose defining trait is the production of botulinum toxin
• Subdivided into four groups based on biochemical tests
  • Group I: proteolytic in culture, and produces toxins A, B, and F
  • Group II: non-proteolytic in culture, and produces toxins B, E, and G
  • Group III: produces toxins C and D
  • Group IV: produces toxin G
• These strains produce eight toxin types, A through G (and possibly H), that are identified by serology; some strains produce two different toxins
  • A, B, E, and F (and possibly H) cause disease in humans
  • Toxins A and B are used therapeutically (e.g. Botox)
  • Toxin G is the only plasmid-encoded toxin

Pathophysiology

• Disease is caused by ingestion or inhalation of preformed toxin, or absorption of toxin from localized infections in the GI tract or a wound
  • Absorbed primarily in duodenum and jejunum
• Botulinum toxins are zinc-dependent metalloproteinases, and inhibit the release of acetylcholine from the presynaptic neuron
  • Affects exclusively cholinergic synapses, including those of the neuromuscular junction and the autonomic nervous system
  • Different toxin types target different specific proteins within the neuro

Life Cycle

• Circulates primarily in birds and non-human mammals

Epidemiology

• Spores are found worldwide in soil and water
• Disease commonly occurs in outbreaks related to contaminated food
  • A is most common in North America and is commonly associate
  • E is associated with marine animals and fish, and is common in outbreaks amongst Inuit people
• More common in certain areas due to local food practices

Clinical Manifestations

• Typically involves symmetric descending paralysis, starting with cranial nerves and often involving respiratory muscles
• Afebrile with normal or slow heart rate despite hypotension, and sparing the sensory nerves
• This presentation contrasts with polio, which can be asymmetric and often has fever

Foodborne Botulism

• Symptoms start 12 to 36 hours after ingestion
• Nausea, diarrhea, and dry mouth
  • Of note, diarrhea is not caused by the toxin but by other ingested contaminants
• Descending flaccid paralysis, with:
  • Acute onset bilateral cranial neuropathies, causing diplopia, dysphagia, and dysarthria
  • Almost always symmetric, but can rarely be asymmetric
  • Autonomic neuropathies, causing dry mouth, fixed or dilated pupils, blurred vision, and hypotension
  • Upper and lower extremity weakness
  • May appear calm despite significant respiratory distress, due to the paralysis
• GI symptoms include constipation, nausea, and vomiting; occasionally abdominal cramps and diarrhea
• Usually fatigue, and occasionally sore throat and dizziness
• No cognitive or sensory effects (rarely paresthesias)

Wound Botulism

• Incubation period of 4 to 14 days
• More commonly caused by toxins A or B
• Classically associated with injection of "black-tar" heroin, especially those who inject by skin-popping
• May have fever secondary to an infected wound, although the wound can rarely appear to be healing well
• Can produce abscesses

Infant Botulism

• Classically after ingesting unpasteurized honey
• Most commonly caused by toxins A, B, and F
• Presents with feeding difficulties, hypotonia, drooling, and weak cry
• Descending paralysis, including upper airway obstruction that may require intubation
• Distinguishing features are lack of fever, normal CSF
• Typically worsens over 1 to 2 weeks, then stabilizes for 2 to 3 weeks, then recovers
• Relapses are possible

Adult Intestinal Toxemia

• Rare form of botulism associated with colonisation of the GI tract
• Most commonly caused by toxin A, but occasionally also B and F
• Onset is more gradual and disease less severe than foodborne botulism
• Risk factors are gastrointestinal surgery or illness, such as inflammatory bowel disease

Inhalation Botulism

• Incubation period of 12 hours to 3 days
• Rare, associated with insufflation of contaminated cocaine, but also a theoretical bioterrorism agent
• Typical symptoms of botulism

Iatrogenic Botulism

• May occur during use of therapeutic botulinum toxin (e.g. Botox)

Prognosis

• Mortality with appropriate treatment is 5 to 8% in adults and 1% in infants
• Takes weeks to months to recover (admissions lasting 1 to 3 months) and may have fatigue and weakness for more than one year

Differential Diagnosis

Adults

• Guillain-Barré syndrome (acute inflammatory demyelinating polyneuropathy): asymmetric, ascending, and involves sensory nerves; or ataxia, in the Miller-Fisher variant that involves cranial nerves
• Lambert-Eaton myasthenic syndrome
• Myasthenia gravis: lacks autonomic features
• Stroke, especially brainstem stroke
• Bacterial or chemical food poisoning
• Tick paralysis: Dermacentor tick still attached
• Chemical intoxication: carbon monoxide poisoning, organophosphate toxicity
• Mushroom poisoning
• Poliomyelitis: typically febrile and asymmetric
• Psychiatric illness

Infants

• Sepsis
• Meningitis
• Electrolyte imbalance
• Reye syndrome
• Congenital myopathy
• Werdnig-Hoffman disease
• Leigh disease

Diagnosis

• Samples should include serum, gastric secretions, stool, or food
• Gold standard for diagnosis is the mouse bioassay
  • A mouse is injected with a sample and is monitored for paralysis
  • Toxin type is determined by administering type-specific antitoxin and monitoring for improvement
• Strict anaerobic cultures of serum, stool, or food, though low sensitivity
• EMG may show small decrement in motor response or brief small abundant motor unit action potentials (BSAP), and may be useful to distinguish botulism from Lambert-Eaton myasthenic syndrome

Management

• Call the Botulism Reference Service for Canada (or equivalent): office (613) 957-0902; laboratory (613) 957-0885; after-hours (613) 296-1139
• Supportive care
  • Low threshold for intubation and ventilation
  • If contaminated food still in gastrointestinal tract, may use purgatives to prevent further absorption (unless ileus)
  • Appropriate debridement and wound care, for wound botulism
• Antitoxin should be given within 2 to 3 days of symptom onset
  • For infants up to 1 year old, BabyBIG (BIG-IV) 50 mg/kg
    • Human-derived
    • Only manufactured in California, so difficult to access urgently
  • For children over 1 year and adults, heptavalent botulinum antitoxin (HBAT)
    • Horse-derived antitoxin to toxins A through G (7,500 U anti-A; 5,500 U anti-B; 5,000 U anti-C; 1,000 U anti-D; 8,500 U anti-E; 5,000 U anti-F; and 1,000 U anti-G)
    • Risk of sensitization or anaphylaxis to horse proteins
• Antibiotics
  • Unclear benefit, but often penicillin G or metronidazole are used for wound botulism
  • Aminoglycosides and tetracyclines can worsen the paralysis of infant botulism, possibly by lysis of Clostridium botulinum in the gut

Prevention

• Food safety practices
  • Safe canning and fermentation practices
  • Toxin is heat labile, though, so cooking food will deactivate the toxin
• Avoiding honey in infants less than 1 year old
  • Possibly also avoiding raw sugar (but not refined sugar), molasses, herbal (chamomile) tea26 and other herbal preparations

Further Reading

• Botulism Reference Service for Canada