Tetanus – Etiology, Pathogenesis, and Treatment

Introduction

  • Tetanus is a disease caused by a neurotoxin produced by species of Clostridium, which damage the central nervous system of the host.

Etiology

  • The causative agent is Clostridium tetani.
  • It is an anaerobic, motile, spore-forming rod that appears like a drumstick under the microscope.
Clostridium tetani
Microscopic image of C.tetani
  • The cells of C. tetani which are sensitive to oxygen, rapidly die when exposed to oxygen.
  • Grow is identified as a film over the surface of agar.
  • Bacteria are proteolytic and unable to ferment carbohydrate.

Pathogenesis

  • C. tetani produce two toxins:
    • Oxygen– labile hemolysin  also called tetanolysin.
    • Plasmid encoded, heat-labile neurotoxin called tetanospasmin.
  • The plasmid carrying the gene for tetanospasmin is non- conjugative.
  • Tetanolysin is similar to hemolysins and streptolysin O.
  • The clinical importance of tetanolysin is unknown because oxygen, as well as serum cholesterol, inhibits the toxin.
  • At the stationary phase of bacterial cell growth, tetanospasmin is formed, releases on cell lysis which causes clinical symptoms of tetanus.
  • Tetanospasmin is an A- B toxin, 150,000- Da peptide in mol wt.
  • By the action of enzyme endogenous protease, it is cleaved into light, A- chain subunit, and heavy B- chains when neurotoxin is released by the cell.
  • Both chains A and B are bonded by a disulfide bond and non-covalent forces.
  • The heavy chain consists of a carbohydrate-binding domain, its carboxyl-terminal portion binds to specific sialic acid receptors e.g., polysialogangliosides and glycoproteins present on motorneurons.

How do tetanospasmin toxins interact with motor neurons?

  • The molecules of toxins are internalized in endosomal vesicles and transported in the neuron axon —-> Motor neuron soma [spinal cord].
  • The endosome becomes acidified which results in a change in conformation in the N- terminus domain of the heavy chain when inserted in the endosome, it provides passage to the light chain into the cytosol.
  • The light chain is zinc endopeptidase, which cleaves the core proteins, involves in the blocking and release of neurotransmitters.
  • The tetanospasmin inactivates the proteins that involve in the regulation of the release of the inhibitory neurotransmitters gamma-aminobutyric acid [GABA].
  • The inactivation of protein caused by toxins leads to unregulated excitatory synaptic activity in the motor neurons, which causes spastic paralysis.
  • The binding of toxin is irreversible, recovery requires the formation of new axonal terminals.

Figure Showing: [A] Normal Action of the inhibitory neurotransmitter [B] Tetanospasmin blocking the release of the inhibitory neurotransmitter

Epidemiology

  • C. tetani are ubiquitous, mainly exists in soil, and might be temporarily colonizing the gastrointestinal tracts of animals as well as humans.
  • Organisms are sensitive to oxygen toxicity but can survive in the sporulated form.
  • It’s a rare disease, few cases have been reported annually because of vaccination
  • In underdeveloped countries, tetanus causes death, where vaccination is unavailable.
  • It has a high mortality rate in neonates and the elderly i.e., about 30% to 50%.

Manifestations

  • The period of incubation of tetanus is few days to weeks.
  • The primary wound or trauma  is infected by C. tetani
    • Tetanus is classified into three types: Generalised Tetanus, Localised Tetanus, Cephalic Tetanus.

Symptoms:

    • In Generalised Tetanus, early symptoms are drooling, sweating, irritability, and constant back spasms termed as opisthotonos.
    • The masseter muscles are involved [trimus], which causes the inability to open the mouth, this state is called lockjaw, which is a common symptom of tetanus.
    • One more characteristic is a sardonic smile that is because of the persistent contraction of the face muscles, which is called risus sardonicus.
Tetanus patient showing symptoms of facial spasms and risus sardonicus
  • In severe cases, symptoms of tetanus involve autonomic nervous systems, which include symptoms like cardiac arrhythmias [irregular heartbeat], change in blood pressure, excessive sweating, and dehydration.
  • Spasms continue to spreads to other muscles, and severe contraction of other muscles occurs which includes the head, arms, legs, and back.
  • Death is usually caused when diaphragm muscle contraction is included, due to which the patient is unable to exhale.
  • Localized Tetanus- Disease and symptoms remain constant to the muscular area of the infection site.
  • Cephalic Tetanus- Initial site of infection is head
  • Neonatal tetanus involves initial infection at the site where the umbilical cord is removed in newborns which later progress into generalized symptoms of tetanus. The mortality rate is more than 90%.
Tetanus patient is showing symptoms of prolonged contraction of muscle

Diagnosis

  • Most diagnosis is carried out, based on the clinical representation.
  • The microscopic examination is advantageous but it’s mainly unsuccessful because clostridium is a slow-growing bacteria and sensitive to oxygen.
  • Both tetanus toxins and antibodies remain undetectable in the patient since toxins are attached to the motor neurons and internalized.
  • If the isolate is obtained in the culture, produced toxins can be verified with a tetanus antitoxin neutralization test which is carried out in mice.

Treatment

  • The treatment requires debridement i.e., removal of the dead skin of the primary wound.
  • Antibiotics are used like penicillin or metronidazole [preferred more] to kill bacteria reduces toxin production.
  • Passive immunization- which neutralizes the tetanus toxin, vaccine requires 3 doses followed by booster doses for 10 years.

Reference and Sources

  • https://www.ncbi.nlm.nih.gov/books/br.fcgi?book=mmed&part=A1131
  • https://en.wikipedia.org/wiki/Tetanus
  • https://quizlet.com/20768684/chapter-39-41-micro-vocab-and-bacteria-flash-cards/
  • https://quizlet.com/437584230/patho-exam-ii-lectures-11-and-12-flash-cards/
  • https://lecture-notes.tiu.edu.iq/wp-content/uploads/2021/05/clostridiUM.pdf

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