Botulism

Botulism is a rare, neuroparalytic syndrome caused by Clostridium botulinum (C. botulinum). A fatal neurotoxin (botulinum toxin) is released causing varying degrees of muscle paralysis and distinct clinical syndromes. The most common types of botulism are foodborne and infant. Botulism presents with blurred vision, respiratory failure, and symmetric, descending flaccid paralysis. Characterization includes intact sensorium, normal heart rate and blood pressure, absence of fever, and absence of sensory deficits. Diagnosis is made on clinical grounds and can be confirmed by the isolation of bacteria or toxins from stool, wound specimens, or food sources. The approach to managing a case of botulism should include prompt management of respiratory failure, administration of antitoxin, and supportive care for paralysis.

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Overview

Definition

Botulism is a rare, neuroparalytic syndrome caused by the bacteria Clostridium botulinum (C. botulinum), which releases a fatal neurotoxin (botulinum toxin), resulting in varying degrees of muscle paralysis and distinct clinical syndromes.

Epidemiology

  • Approximately 1,000 cases per year (rare disease)
  • Can occur in any age group
  • No person-to-person transmission
  • C. botulinum is found in soil and marine sediments worldwide.
  • The most common types are foodborne and infantile botulism. 
  • The least common type is adult intestinal toxemia.

Etiology

  • Pathogen C. botulinum:
    • Gram-positive bacillus
    • Anaerobic, spore-forming bacteria
    • Found in soil and marine sediments worldwide
    • 4 distinct phenotypes: I–IV
  • Botulinum toxin:
    • Neurotoxic protein produced by C. botulinum
    • Classified into 7 serotypes: A–G
    • A, B, E, and F cause disease in humans.
    • A and B are used commercially and medically.
    • Blocks the release of the neurotransmitter acetylcholine (ACh) at the neuromuscular junction (NMJ)
  • Conditions favorable for pathogen growth and spore formation:
    • Low O2 or no O2 (anaerobic conditions)
    • pH of 7 and above
    • Ideal temperature range: -25℃–37℃
    • Survive in temperatures as low as 4℃  and as high as 100℃

A photomicrograph of C. botulinum bacteria

Image: “Clostridium botulinum” by CDC. License: Public Domain

Classification

Infant botulism

  • Mode of infection: ingestion of C. botulinum spores
  • The toxin is produced in vivo (bacteria germinate in the GI tract).
  • Common occurrence in infants < 6 months of age (natural defenses have not yet developed in the intestine)
  • The most common product causing infant botulism is raw honey.

Foodborne botulism

  • Mode of infection: ingestion of food contaminated with C. botulinum toxin
  • Commonly found in inadequately canned foods with low-acid content and lightly preserved food products (e.g., fermented, salted, or smoked meat products)
  • Dangerous: may infect many people at once who consume food from the same source

Wound botulism

  • Mode of infection: Spores of C. botulinum enter an open wound and thrive under anaerobic conditions.
  • Rare form of botulism
  • Can result from contamination of the wound by soil, gravel, or inappropriately treated open fractures
  • Commonly associated with substance abuse of black tar heroin

Iatrogenic botulism

  • Mode of infection: botulinum toxin injections for cosmetic or therapeutic/medical purposes (e.g., migraine, contractures, spasticity)
  • Another rare form of botulism
  • A highly concentrated preparation of the toxin can cause iatrogenic botulism.

Adult intestinal toxemia

  • Mode of infection: ingestion of spores of C. botulinum
  • Least common form of botulism 
  • Similar to infantile botulism but occurs in older children and adults with bowel abnormalities or disruption of the normal intestinal flora (e.g., inflammatory bowel disease)

Inhalation botulism

  • Does not occur naturally
  • Associated with the accidental or intentional release of toxin in aerosols (bioterrorism associated botulism)
  • Clinical presentation is similar to foodborne botulism.
  • A lethal dose is 2 ng/kg of bodyweight.

Pathophysiology

The means of exposure to the toxin will determine the type of botulism; the toxin is not absorbed through intact skin.

Exposure can occur through the following mechanisms:

  • Ingestion of preformed toxin
  • Inhalation of preformed toxin
  • Production of toxin by C. botulinum in the GI tract
  • Production of toxin by C. botulinum in devitalized tissue at the site of a wound
  • Exposure to the toxin by injection for cosmetic or therapeutic/medical purposes

Mechanism of pathogenesis:

  • Botulinum toxin is activated by proteolytic cleavage in the circulation and transported to the neuromuscular junction (NMJ).
  • Botulinum toxin exists in the circulation as a polymer of a light chain and a heavy chain.
  • The heavy chain of the toxin binds to receptors on the presynaptic neuron and enters the presynaptic neuron via receptor-mediated endocytosis.
  • Once inside the endocytotic vesicles of the presynaptic neuron, the light chain of the toxin crosses the membrane of the endocytotic vesicle and enters the cytoplasm.
  • Once in the cytoplasm, the light chain binds SNARE/SNAP proteins, which are involved in the release of ACh from the presynaptic vesicles where it is stored.
  • The inhibition of ACh release prevents ACh from binding to the ACh receptor, which halts muscle contraction and leads to weakness/paralysis.

Effect of botulinum toxin at the level of the NMJ: inhibition of ACh release

Image by Lecturio.

Clinical Presentation

General characteristics

The classic presentation of botulism includes symmetric cranial nerve palsies and descending paralysis. The 5 key features of botulism include: 

  1. Absence of fever
  2. Symmetric neurological deficits: symmetric, descending flaccid paralysis of voluntary muscles (begins as proximal muscle weakness and progresses distally)
  3. Intact sensorium and mental status
  4. Normal or slow heart rate and normal blood pressure
  5. No sensory deficits (except blurred vision)

Cranial neuropathies are common in all types of botulism. The classic presentation includes the “4 Ds” (bulbar symptoms):

  1. Diplopia: The 1st clinical symptom/sign is often extraocular involvement.
  2. Dysarthria
  3. Dysphonia
  4. Dysphagia

Botulism does present with autonomic findings:

  • Pupillary (dilated, fixed pupils)
  • Reduced salivation
  • Reduced lacrimation
  • Paralytic ileus/severe constipation
  • Gastric dilatation
  • Bladder distention/urinary retention
  • Orthostatic hypotension

Infant botulism

  • Incubation period: 3–30 days after spore entry
  • Commonly occurs in infants < 6 months of age
  • Constipation: often the 1st sign
  • Drooling
  • Weak cry
  • Irritability
  • Seizures
  • Floppy baby syndrome:
    • Bilateral ptosis
    • Loss of head control, floppy movements/hypotonia
    • General weakness/lethargy
    • Poor feeding (weak sucking)

An important presentation in infant botulism: floppy baby syndrome

Image by Lecturio.

Foodborne botulism

  • Incubation period: 12–36 hours after toxin consumption
  • Prodromal symptoms:
    • Nausea, vomiting, diarrhea, and abdominal cramps
    • Initial diarrhea (direct toxin effect in GI endothelium) progresses to constipation (as systemic NMJ manifestations dominate).
  • Dry mouth
  • Difficulty swallowing or speaking 
  • Symmetric facial weakness
  • Blurred vision
  • Cranial neuropathies
  • Difficulty breathing

Wound botulism

  • Incubation period difficult to estimate (timing of exposure usually uncertain)
  • Symptoms are similar to foodborne botulism, except prodromal symptoms are absent.
  • Wound botulism presents with fever and leukocytosis in around 50% of cases; other forms of botulism do not typically present with a fever
  • Difficulty swallowing or speaking
  • Symmetric facial weakness
  • Blurred or double vision
  • Ptosis
  • Difficulty breathing
  • Descending paralysis
  • Inflammation at the site of the wound

Ptosis in a child with botulism: The patient is alert and oriented.

Image: “Botulism1and2” by Herbert L. Fred, MD and Hendrik A. van Dijk. License: CC BY 2.0

Iatrogenic botulism

  • After injection of botulinum toxin for cosmetic or therapeutic/medical purposes
  • Ptosis
  • Difficulty speaking
  • Paralysis of face
  • Thick and weak tongue
  • Reduced gag reflex

Adult intestinal toxemia

  • Similar to infant botulism but occurs in older children and adults 
  • Constipation
  • Anorexia
  • Lethargy
  • Descending paralysis 
  • Ptosis

Inhalation botulism

  • Symptoms are similar to foodborne botulism.
  • Can develop early and quickly progress to respiratory failure
  • Diarrhea 
  • Dry mouth
  • Difficulty swallowing or speaking 
  • Symmetric facial weakness
  • Blurred vision
  • Cranial neuropathies
  • Difficulty breathing

Diagnosis

History

  • Consumption of canned foods
  • Symptoms similar in individuals with similar exposure
  • History of injectable drug abuse
  • History of cosmetic/medical use of botulinum toxin
  • Acute onset of floppy baby syndrome symptoms
  • History of honey consumption in babies

Physical examination

  • Acute onset of symptoms of cranial neuropathy 
  • Symmetric descending weakness
  • Absence of fever
  • Alert and conscious patient with neurologic symptoms

Confirmation of diagnosis

  • Isolation of C. botulinum from stool, wound specimen, or food source
  • ELISA or PCR detection of toxin in serum, stool, vomit, or food source
  • Other tests:
    • MRI or CT: to rule out other reasons for neurologic symptoms (e.g., stroke)
    • CSF exam: to rule out meningitis 
    • Electromyography (EMG): for suspected infant botulism 
    • Tensilon test: 
      • To rule out myasthenia gravis
      • Not conducted at present (unavailable in the United States) because of a high occurrence of false-positive results

Management

A detailed clinical history and diagnosis are important in botulism as the tests take time. If a case history is highly suggestive of botulism, treatment should not be delayed.

General approach

  • Hospitalization
  • Monitor for signs of respiratory failure:
    • Pulse oximetry
    • Spirometry
    • Arterial blood gas measurement
    • If inadequate/worsening upper airway competency, or in patients with a vital capacity < 30%, prompt intubation is indicated.
  • For supportive care, provide nasogastric feeding in small amounts to prevent aspiration.
  • Administration of antitoxin

Antitoxin

Antitoxin is the mainstay of botulism treatment. Two major forms are available in the United States:

Heptavalent botulinum antitoxin:

  • Equine serum heptavalent antitoxin: contains antibodies against 7 types of botulinum toxin 
  • Binds to circulating neurotoxins and prevents NMJ binding
  • The antitoxin cannot reverse paralysis but can prevent paralysis progression. 
  • Antitoxin administration within 24 hours of the onset of symptoms is preferred.
  • Dosing considerations:
    • Adults: 1 vial
    • Children 1–17 years of age: 20%–100% of the adult dose
    • Infants < 1 year of age: 10% of the adult dose
  • Anaphylaxis is an adverse effect (skin testing before administration is a good precautionary measure).

Human botulinum immunoglobulin (BIG-IV):

  • Preferred management for infants < 1 year diagnosed with infant botulism
  • IV administration
  • No serious adverse effects have been reported yet.

Type-specific therapy

  • Foodborne botulism: In the absence of ileus, laxatives and enemas can be considered to eliminate the toxin and relieve constipation.
  • Infant botulism: 
    • Administer BIG-IV as soon as possible.
    • Strictly avoid antibiotics in infant botulism. 
  • Wound botulism: 
    • Extensive debridement of the wound is important. 
    • If 5 years or more since the last immunization, tetanus boosters are considered.
    • Penicillin G and metronidazole are the preferred antibiotics for mixed infections.
    • Aminoglycosides, polymyxins, and tetracycline are avoided (may induce neuromuscular blockade).

Experimental therapies

  • Pyridostigmine and/or guanidine induce the release of ACh at the NMJ.
  • Plasmapheresis

Physiotherapy

  • Breathing exercises:
    • Respiratory failure is the major cause of death in botulism.
    • Diaphragmatic controlled breathing: maintains the respiratory cycle
    • Pursed lip breathing: improves gas mixing at rest and prevents premature airway collapse
  • Range of motion exercises: keeps the joints moving and retains muscle function 
  • Strengthening exercises: maintains function in the muscles

Differential Diagnosis

  • Myasthenia gravis: an autoimmune neuromuscular disorder characterized by varying degrees of muscle weakness in the arms and legs. Presentation also includes ptosis, dysphagia, fatigue, and breathlessness. Diagnosis is through a tensilon test and specific antibody detection. Myasthenia gravis is managed medically with steroids and surgically by thymectomy. 
  • Lambert-Eaton syndrome: an autoimmune neuromuscular syndrome often associated with small cell lung carcinoma. Symptoms include ptosis, dry mouth, bladder and bowel changes, erectile dysfunction, paresthesia, and weakness of muscles, which is temporarily relieved on exertion. Diagnosis includes antibody detection, EMG, X-ray, and lung CT. Treatment includes resolving the underlying cause and immunosuppressants. 
  • Guillain-Barré syndrome: a disorder of the peripheral nervous system triggered by an acute bacterial or viral infection. Presentation includes initial paresthesia in the feet and legs with progression to ascending paralysis. Additional symptoms include walking abnormalities, fatigue, tachycardia, hypertension, and urinary retention. Diagnosis is by CSF analysis, EMG, and nerve conduction studies. Guillain-Barré syndrome is managed with plasmapheresis and immunoglobulin therapy, analgesics, blood thinners, and physiotherapy.
  • Stroke: a medical emergency causing damage to the brain due to interrupted blood supply. Presentation includes headache, dysarthria, blurred vision, facial paralysis, and numbness of the face, arms, and legs. Stroke is diagnosed by physical exam, CT, MRI, cerebral angiogram, or carotid ultrasound. Management depends on the type of stroke (ischemic or hemorrhagic). 
  • Tick paralysis: occurs due to injection of toxin by the bite of a tick. Symptoms occur within 2–7 days. Clinical presentation includes initial numbness and weakness in both legs with progression to ascending paralysis and respiratory distress within hours. Deep tendon reflexes are decreased or absent. Diagnosis is based on symptoms and finding an embedded tick (usually on the scalp). The disease is managed by detecting and removing the tick, cleaning the site of the bite, and monitoring for respiratory distress.

References

  1. CDC. (2006). Botulism: Epidemiological Overview for clinicians. Retrieved April 13, 2021, from https://www.emergency.cdc.gov/agent/botulism/clinicians/epidemiology.asp#:~:text=An%20average%20of%20110%20cases,and%20women%20are%20affected%20equally.
  2. WHO. (2018). Botulism. Retrieved April 13, 2021, from https://www.who.int/news-room/fact-sheets/detail/botulism
  3. P Samuel Pegram, Sean M Stone. (2021). Botulism. UpToDate. Retrieved April 13, 2021, from https://www.uptodate.com/contents/botulism
  4. Longo, Fauci, Kasper, Hauser, Jameson Loscalzo. (2011). Infectious diseases – diseases caused by gram-positive bacteria. (Pg 2544 – 2551). Harrison’s Principles of Internal medicine (18th edition).

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