Tetanus

Tetanus is a bacterial infection caused by Clostridium tetani, a gram-positive obligate anaerobic bacterium commonly found in soil that enters the body through a contaminated wound. C. tetani produces a neurotoxin that blocks the release of inhibitory neurotransmitters and causes prolonged tonic muscle contractions. It presents with lockjaw, neck stiffness, opisthotonus, rigid abdomen and severe painful muscle spasms. Diagnosis is made on clinical grounds, as it is rarely possible to isolate the infectious agent from the wound. It is treated with antibiotic therapy and the human tetanus antitoxin. Untreated tetanus can lead to respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure and cardiovascular complications and can be fatal. With appropriate treatment, however, most patients will recover.

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Overview

Definition

Tetanus is a nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System disorder caused by the bacterium Clostridium tetani.

Etiology

  • Pathogen: Clostridium tetani:
    • Gram-positive bacillus Bacillus Bacillus are aerobic, spore-forming, gram-positive bacilli. Two pathogenic species are Bacillus anthracis (B. anthracis) and B. cereus. Bacillus
    • Spore-forming, obligate anaerobe
    • 10 serotypes have been identified.
    • All 10 of the serotypes contain 2 common toxins: tetanolysin and tetanospasmin
  • Toxins:
    • Tetanolysin causes local tissue destruction but is not relevant to the pathogenesis of tetanus.
    • Tetanospasmin is a potent neurotoxin (exotoxin) that causes clinical tetanus.
  • Habitat:
    • Soil
    • Freshwater
    • Marine sediments
    • Intestinal tract of humans and animals
    • Spores can be airborne.
Micrograph of group of clostridium tetani bacteria

The micrograph depicts a group of Clostridium tetani bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, responsible for causing tetanus in humans:
Note the slender bacillus Bacillus Bacillus are aerobic, spore-forming, gram-positive bacilli. Two pathogenic species are Bacillus anthracis (B. anthracis) and B. cereus. Bacillus with a characteristic “drumstick” appearance caused by the spherical terminally located spores.

Image: “This micrograph depicts a group of Clostridium tetani bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, responsible for causing tetanus in humans” by CDC. License: Public Domain

Epidemiology

  • Can occur in any age group, but neonates are the age group at highest risk. 
    • Neonatal tetanus is extremely dangerous; it has a mortality rate of nearly 100%.
    • Occurs mainly in developing countries with unclean delivery techniques and poor postnatal hygiene
  • Most cases of tetanus occur in countries where there is a lack of immunization.
  • Elderly individuals are also at risk because of reduced immunity.
  • Spores of C. tetani are present in the soil irrespective of geographical location.

Mode of infection

  • Through contaminated wounds (most common)
  • Complication of IV drug use
  • Through the middle ear (cephalic tetanus)
  • Through the umbilical stump (neonatal tetanus)
  • Risk factors for developing tetanus: 
    • Burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns
    • Surgical wounds
    • IV drug use
    • Diabetes
    • Immunosuppression

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Pathophysiology

Types

  • Generalized tetanus: most common and severe form
  • Local tetanus: mild form with symptoms that develop only near the infected wound
  • Cephalic tetanus: rare but fatal infection that usually enters through the middle ear
  • Neonatal tetanus: due to infection of the umbilical stump

Pathophysiology

Inoculation:

  • C. tetani has little invasive power.
  • Spores usually enter the organism through contaminated wounds.
  • Not every inoculation will result in infection.
  • Spores germinate under anaerobic conditions: wound ischemia, tissue necrosis, devitalized tissue
  • Average incubation period is 7–10 days (can last from 1 to 60 days).
  • Neonatal tetanus usually presents with a shorter incubation period (5–7 days after birth).

Pathogenesis:

  • Exotoxins (tetanospasmin and tetanolysin) are produced by germinated bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview.
  • Tetanolysin may play a role in local tissue destruction, but tetanospasmin is responsible for the neurologic symptoms.
  • Tetanospasmin is released into the blood and enters the presynaptic terminals of the neuromuscular end plate of motor neurons.
  • Inhibit release of GABA and glycine (inhibitory neurotransmitters)
  • Toxin then travels to the CNS via retrograde axonal transport, where it also blocks GABA and glycine release.
  • A lack of inhibitory neurotransmitters causes a continuous excitatory state of the motor neuron → spastic paralysis
  • Continuous unopposed muscle activity can lead to bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones fractures and muscle tears.
Pathophysiological mechanism caused by clostridium tetani

Pathophysiologic mechanism caused by Clostridium tetani:
Tetanospasmin blocks the binding of neurotransmitters (GABA/glycine) to their receptors on the postsynaptic membrane, leading to inhibitory neurotransmission Neurotransmission The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. The plasma membranes of the 2 neurons are placed very close together, and the space between the 2 neurons is called the synaptic cleft. The molecules that mediate the interaction are called neurotransmitters. Synapses and Neurotransmission

Image by Lecturio.

Clinical Presentation and Diagnosis

Clinical presentation

Generalized tetanus is the most common and severe clinical form of tetanus.

  • General malaise
  • Trismus, or lockjaw (80%): 
    • Caused by spasm of the masseter muscles, which causes difficulty in opening the mouth and difficulty in mastication
    • The most important early symptom; preceded by general malaise
    • Spasms may be triggered by visual, auditory, and mechanical stimuli.
  • Stiffness of the neck
  • Risus sardonicus, or sardonic smile:
    • Due to tonic rigidity involving muscles of the face Muscles of the Face The facial muscles (also called mimetic muscles) control facial expression and are supplied by the facial nerve. Most of them originate from the skull and attach to the skin around the facial openings, which serve as a method to group or classify them. Muscles of the Face, neck, and trunk
    • Contraction of the frontalis muscles and muscles of the angle of the mouth produces a characteristic grinning expression.
  • Opisthotonus:
    • A varying degree of rigidity develops in the muscles of the neck Muscles of the Neck The muscles of the neck can be divided into 3 groups: anterior, lateral, and posterior neck muscles. Each of the groups is subdivided according to function and the precise location of the muscles. Muscles of the Neck, back, and trunk.
    • The back is usually arched, and the abdominal wall appears broad.
  • Rigid abdomen
  • Convulsions: 
    • Painful, violent, exhausting, reflex spasms that last for 3–4 minutes
    • Develop within 24–72 hours after the initial onset of symptoms
  • Laryngeal spasm: causes difficulty breathing
  • Esophageal spasm: causes dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia
  • Urethral spasm: causes urinary retention
  • Autonomic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System overactivity:
    • Sweating
    • Tachycardia
    • Fevers
    • Cardiovascular complications: labile blood pressure, arrhythmias

Neonatal tetanus: 

  • Refusal to feed and difficulty opening the mouth due to trismus in an infant previously able to feed and cry properly
  • Poor sucking
  • Irritability
  • Grimacing
  • Clenched hands and dorsiflexed feet
  • Intense rigidity and spasms can lead to opisthotonus.
Body rigidity in neonatal tetanus

Neonate displaying body rigidity seen in neonatal tetanus

Image: “Neonatal tetanus 6374” by CDC. License: Public Domain

Local tetanus

  • Tonic contractions/spasms limited to one body region/extremity
  • Will often progress to generalized tetanus

Cephalic tetanus: 

  • Rare, but frequently fatal
  • Trismus
  • Peripheral facial paralysis (facial nerve most commonly involved)
  • Ophthalmoplegia
  • Dysphagia
  • Can progress to generalized tetanus

Diagnosis

  • Diagnosis is made on clinical grounds, as it is difficult to isolate C. tetani from its original site of entry.
  • History:
    • History of a previous tetanus-prone injury
    • History of inadequate immunization for tetanus
    • History of immunosuppression or presence of risk factors
  • Physical exam: 
    • Presence of characteristic findings
    • “Spatula test”: Touching the back of the throat elicits jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint contraction instead of normal gag reflex.
  • Serum antitoxin level:
    • Not always readily available
    • Level ≥ 0.01 IU/mL makes tetanus less likely.

Management

Supportive management:

  • Toxin bound to synaptic endings cannot be neutralized.
  • The effects of toxin can, therefore, last for weeks, and supportive management is required.
    • ICU admission
    • Endotracheal intubation is frequently needed to protect airway.
    • Tracheostomy may be needed if prolonged intubation is required.
    • Maintenance of hydration
    • Enteral feeding to maintain nutrition
    • Prophylaxis against thromboembolism by the administration of anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants
    • Prevention and treatment of secondary infections
    • Physical therapy after the cessation of spasms
    • Control of muscle spasms:
      • Place the patient in a quiet room and avoid unnecessary stimuli.
      • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines/IV diazepam
      • Baclofen is used in a few cases.
    • Management of autonomic dysfunction:
      • Magnesium sulfate
      • Labetalol

Halting production of toxin:

  • Debride wound to lower bacterial counts.
  • Antibiotic therapy: 
    • Metronidazole (best choice) for 7–10 days
    • Penicillin
    • Doxycycline
    • Cephalosporins Cephalosporins Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with "cef-" or "ceph-." Cephalosporins if co-infection with another organism is suspected

Neutralization of unbound toxin:

  • IM human tetanus immunoglobulin (HTIG) is administered and infiltrated around the wound.
  • If HTIG is not available, then intravenous immunoglobulin may be administered.
  • In countries where HTIG is not readily available, IM equine tetanus immunoglobulin can be administered.
  • Because of high chances of allergic reaction with equine immunoglobulin, a test dose should be administered.

Complications

  • Fractures: Severe spasms can lead to fractures in the vertebrae and other bones.
  • Laryngospasm: 
    • A brief spasm of the larynx Larynx The larynx, also commonly called the voice box, is a cylindrical space located in the neck at the level of the C3-C6 vertebrae. The major structures forming the framework of the larynx are the thyroid cartilage, cricoid cartilage, and epiglottis. The larynx serves to produce sound (phonation), conducts air to the trachea, and prevents large molecules from reaching the lungs. Larynx, usually lasting 30–60 seconds
    • Laryngospasm prevents oxygen from reaching the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs, making breathing difficult.
    • In severe cases, laryngospasm leads to asphyxia and ultimately death.
  • Aspiration pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: Tetanus causes muscle rigidity, leading to difficulty in coughing and swallowing, which can result in aspiration pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia.
  • Acute renal failure:
    • Severe muscle spasms associated with tetanus can cause rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis.
    • Rhabdomyolysis results in the excretion of myoglobin in the urine, leading to acute kidney failure.
  • Complications of prolonged immobilization:
    • Deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis and pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism
    • Nosocomial infections

Prophylaxis

  • Tetanus is a vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination-preventable disease.
  • Tetanus vaccines are based on tetanus toxoid and are available as single or combination vaccines.
  • Combined diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria–tetanus– pertussis Pertussis Pertussis, or whooping cough, is a potentially life-threatening highly contagious bacterial infection of the respiratory tract caused by Bordetella pertussis. The disease has 3 clinical stages, the second and third of which are characterized by an intense paroxysmal cough, an inspiratory whoop, and post-tussive vomiting. Pertussis (Whooping Cough) vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination is administered as a part of the normal immunization schedule, which provides protection up to adolescence.
  • Administered to pregnant women and those of childbearing age to prevent neonatal tetanus
  • Patients presenting with wounds:
    • Clean wounds: administer vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination:
      • If < 3 previous doses
      • If last dose > 10 years ago
    • Contaminated wounds:
      • Give vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination if last dose > 5 years ago
      • Human tetanus immune globulin if < 3 doses of toxoid vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination
  • For patients affected with tetanus:
    • Immunity following tetanus is incomplete and does not prevent recurrent episodes.
    • A full schedule of active immunization is therefore instituted with tetanus and diphtheria Diphtheria Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria toxoid–containing vaccines.
Prophylaxis of tetanus

Wound management and prophylaxis of tetanus:
The time from the last dose determines the treatment given to an individual to prevent contracting the disease.
Immunity categories:
A: The patient has had a complete course of toxoid or a booster within the past 5 years.
B: The patient has had a complete course of toxoid or a booster between 5 and 10 years ago.
C: The patient has had a complete course of toxoid or a booster dose > 10 years ago.
D: The patient has not had a complete course of toxoid or immunity status is unknown.

Image by Lecturio.

Prognosis

  • The majority of those affected will recover with appropriate care.
  • Shorter incubation periods are associated with more severe disease.
  • In resource-limited countries, the case fatality ranges from 5% to 50%.
  • Neonatal tetanus has mortality rates of 3%–88%.
  • Residual neurologic deficits are common in survivors.

Differential Diagnosis

  • Strychnine poisoning: Strychnine is a toxic alkaloid used in pesticides. After ingestion, patients present with symptoms of muscle spasms, cramping, stiffness, agitation, tachycardia, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, tachypnea, mydriasis, and nystagmus. Diagnosis is by a thorough history and laboratory assays of blood, urine, and tissue. There is no specific treatment; only supportive management is required.
  • Phenothiazine overdose: Phenothiazine is a drug used to treat schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia. Symptoms of overdose include deviation of eyes, writhing movements of head and neck, drooling, and shallow breathing. Diagnosis is by detailed history and blood and urine analysis. Treatment is by the administration of the anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs agent benztropine.
  • Tetany: carpopedal spasms, muscle cramps, tremors or spasms of the face, and calf muscles: Tetany is caused by hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia secondary to an underlying disorder or deficiency. Diagnosis is by blood analysis and the presence of 2 clinical signs: Chvostek and Trousseau. Treatment is by the administration of calcium gluconate and resolution of the underlying cause.
  • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis: an inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges commonly caused by bacterial and viral infections: Symptoms include headache, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, stiff neck, and lethargy, as well as refusal to feed and irritability in infants. Diagnosis is by blood analysis and spinal tap. Treatment includes antibiotics or antiviral therapy and supportive management.

References

  1. George EK, De Jesus O, Vivekanandan R. (2020). Clostridium tetani. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK482484/
  2. Boloor A, Nayak R. (2018). Exam Preparatory Manual for Undergraduates Medicine. 2nd ed. Xxxxx: Xxxxx, p. 122.
  3. Bourget D. (2020). Tetanus. StatPearls. Retrieved March 12, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/29997/
  4. Ralston SH, et al. (Eds.). (2018). Davidson’s Principles and Practice of Medicine, 23rd ed. Xxxxx: Xxxxx, pp. 1125–1126.
  5. World Health Organization. (2021). Tetanus Disease and Epidemiology. Retrieved March 12, 2021, from http://www.emro.who.int/health-topics/tetanus/vaccine-vaccination.html
  6. Thwaites L. (2020). Tetanus. UpToDate. Retrieved March 12, 2021, from https://www.uptodate.com/contents/tetanus#H1917381

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