Tetanus

Etiology

Tetanus is due to infection from the bacterium, Clostridium tetani, which is found in soil, dust, or animal feces. It is a gram-positive, spore-forming, obligate anaerobic bacillus. This bacteria and its spores are found worldwide, however, it is more frequently found in hot and wet climates where the soil is rich with organic matter.

C. tetani may enter the human body through wound puncture, laceration, skin breaks, or inoculation with an infected syringe or insect bites. The most common source of infection is a wound that is often trivial and may go unnoticed, such as a minor laceration from wood or metal splinters or thorns. High-risk populations include those that have not been vaccinated, intravenous drug users, and those who are immunosuppressed. Other causes of infection have been documented through surgical procedures, intramuscular injections, open fractures, dental infections, and dog bites.[5][6][7]

Tetanus spores are durable and can survive for prolonged periods in certain environments. The source of infection, in most cases, is a wound, usually from a minor injury. A very common cause of tetanus is a lack of immunization. Even those who are vaccinated lose immunity with advancing age.

Tetanus can also develop as a consequence of chronic conditions such as abscesses and gangrene. Furthermore, burn patients and patients undergoing surgery can also acquire the infection.

Tetanus usually occurs in persons who are not immunized, partially immunized, or fully immunized but lack adequate booster doses.[8]

The risk factors for neonatal tetanus include the following:

1. Unvaccinated mother
2. Home delivery
3. Septic cutting of the umbilical cord
4. Neonatal tetanus in a previous child
5. Infectious substances applied to the umbilical stump, such as animal dung, mud, or other such material

Epidemiology

Although tetanus affects people of all ages; however, the highest prevalence is seen in newborns and young persons.[9] The World Health Organization (WHO) reports improvement in mortality rates from tetanus, associated with aggressive vaccination campaigns in recent years. The WHO estimates worldwide tetanus deaths in 1997 at around 275,000 with improved rates in 2011 at 14,132 cases. However, of these cases, the prevalence of tetanus is still disproportionately higher (some studies showing 135 times higher) in low-resource settings than rates in developed countries, with mortality rates of 20% to 45% with the infection. Mortality rates vary based on the availability of resources, notably mechanical ventilation, invasive blood pressure monitoring, and early treatment.[10]

The incidence of neonatal tetanus is decreasing due to routine vaccination worldwide, which is combined with other vaccines, pertussis, and diphtheria (DPT). The occurrence of tetanus among neonates is mostly due to incomplete vaccination of the infant. In 2013, approximately 84% of children less than 12 months of age had coverage of tetanus worldwide.

In high-resource countries, such as the United States, cases of tetanus occur in the unimmunized or in the elderly who have decreased immunity over time. Intravenous drug users are also at risk owing to contaminated needles or drugs.

Tetanus is a disease of the underdeveloped world. It is more commonly found in areas where the soil is cultivated, in warm climates, and among males. It is also more frequently seen in neonates and children in countries where there is no immunization program in place.[11]

Pathophysiology

C. tetani secretes the toxins, tetanospasmin, and tetanolysin, causing the characteristic “tetanic spasm,” a generalized contraction of agonist and antagonistic muscles. Specifically, tetanospasmin affects the nerve and muscle motor endplate interaction, causing the clinical syndrome of rigidity, muscle spasms, and autonomic instability. On the other hand, tetanolysin damages the tissues.

At the site of inoculation, tetanus spores enter the body and germinate in the wound.[12] Germination needs particular anaerobic conditions, such as dead and devitalized tissue that has low oxidation-reduction potential. After germination, they release tetanospasmin into the bloodstream.[13] This toxin enters the presynaptic terminals in the neuromuscular endplate of motor neurons and destroys a vesicular synaptic membrane protein resulting in the inactivation of inhibitory neurotransmission that usually suppresses motor neuron and muscle activity. This paralyzes muscle fibers. Subsequently, this toxin, via retrograde axonal transport, travels to neurons in the central nervous system, where it also inhibits neurotransmitter release; this occurs approximately 2 to 14 days after inoculation. Since glycine and GABA are major inhibitory neurotransmitters, cells fail to inhibit the motor reflex response to sensory stimulation, causing a tetanic spasm. This can cause such powerful unopposed muscle activity and contraction that bone fractures and muscle tears can occur.

The incubation period can last from one to 60 days but is, on average, around 7 to 10 days. Symptom severity depends on the distance from the central nervous system, with more severe symptoms associated with shorter incubation periods. Once the neurotoxin enters the brainstem, autonomic dysfunction occurs, typically in the second week of symptom onset. With the loss of autonomic control, patients can present with labile blood pressure and heart rate, diaphoresis, bradyarrhythmias, and cardiac arrest. Symptoms can last for weeks to months, with a mortality rate of 10% in those infected; it is even higher in those without prior vaccination. There have been frequent motor and long-term neuropsychiatric complications in survivors; however, many make full recoveries.[14]

History and Physical

The majority of cases of tetanus in the United States are reported in patients who are either unimmunized or partially immunized. The median period of incubation is 7 days and for the majority of cases, it is from 4 to 14 days. The patients sometimes recall the injury but more commonly the injury goes unnoticed.

The clinical features of tetanus include lockjaw, grimace facial expression (risus sardonicus), generalized muscle spasms associated with severe pains, drooling, uncontrolled urination and defecation, and back arching spasm (opisthotonus) that may cause respiratory distress. Most commonly, trismus appears as the first symptom, with the progression of spasms throughout the rest of the body. Reflex spasms occur in most patients and can be triggered by nominal external stimuli, such as noise, touch, or light.

There are four forms of tetanus based on clinical findings: generalized, neonatal, localized, and cerebral tetanus.

Generalized tetanus is the most common form of tetanus, occurring in approximately 80% of cases. Patients present with a descending pattern of muscle spasms, first presenting with lockjaw, and risus sardonicus (rigid smile because of sustained contraction of facial musculature). This can progress to a stiff neck, difficulty swallowing, and rigid pectoral and calf muscles. These spasms can occur for up to 4 weeks, with full recovery taking months. Autonomic instability can also occur in these patients with fever, dysrhythmia, labile blood pressure and heart rate, respiratory difficulties, catecholamine excretion, and even early death.

Neonatal tetanus is a generalized form of tetanus that occurs in newborns of unimmunized mothers or from infection through a contaminated instrument when cutting the umbilical cord. Infants of immunized mothers generally do not get tetanus due to passive immunity from the mother. Those who are infected, exhibit irritability, poor feeding, facial grimacing, rigidity, and severe spastic contractions triggered by touch. There have been case reports of long-term consequences in survivors of neurodevelopmental impairments, behavioral problems, and deficits in gross motor, speech, and language development.

Localized tetanus and cephalic tetanus are the rarest forms of tetanus. Localized tetanus is the persistent contraction of muscles at the site of injury that can persist for weeks. This type is uncommonly fatal; however, it can progress to the generalized form of tetanus, which is more life-threatening. Cephalic or cerebral tetanus is limited to the muscles and nerves of the head. Cephalic tetanus occurs most commonly after head trauma such as a skull fracture, head laceration, eye injury, dental procedures, otitis media, or from another injury site. It presents with neck stiffness, dysphagia, trismus, retracted eyelids, deviated gaze, and risus sardonicus. The facial nerve is most frequently involved. However, other cranial nerves can also be affected. These findings can lead to further complications such as broncho-aspiration, paralysis of respiratory and laryngeal muscles, and respiratory failure. This type can also progress to generalized tetanus.

Physical examination findings can vary significantly from one patient to another. Spatula test is one of the exam techniques that may provide a clue towards the diagnosis. It includes the stimulation of the posterior pharyngeal wall that elicits the reflex spasm of the masseter muscles causing the patient to bite down instead of gag.

Autonomic involvement leads to hypertension and tachycardia alternating with hypotension and bradycardia. In extreme cases, cardiac arrest may also occur.

Patients may also present with abdominal tenderness and guarding, and that may be mistaken for acute abdomen by the providers. Historically, exploratory laparotomies have been performed before making the correct diagnosis.

Cephalic tetanus, although a rare form of tetanus, may present with various cranial nerve palsies. The most commonly involved nerve is the 8th cranial nerve.

Evaluation

The diagnosis of tetanus is clinical with no particular laboratory test. Providers may find a positive wound culture and the isolation of the organism; however, this occurs in only 30% of cases. Key features to note when diagnosing tetanus include acute onset and muscle contractures with generalized spasms without any other medical cause. Some patients can recall a history of injury, but not all.

An assay for antitoxin levels, though not readily available, may help in excluding the possibility of tetanus. A serum antitoxin level of 0.01 IU/mL or higher is generally accepted as protective, making the possibility of tetanus less likely.

Spatula test that has been described before shows high specificity and sensitivity for the clinical diagnosis of tetanus. This involves using a soft-tipped instrument to touch the posterior pharyngeal wall. If this elicits an involuntary jaw contraction instead of the normal gag reflex, this suggests a positive test.

It is important to note that infections occur in people with no immunity or low serum levels of anti-tetanus antibodies. Life-threatening complications from tetanus can occur and include pneumonia secondary to aspiration, laryngospasm, rhabdomyolysis, upper gastrointestinal bleed, cardiovascular instability such as transient cardiac arrest, tachycardia, or bradycardia, arrhythmias, hypertension, acute renal failure, and secondary wound infections. Mortality from the infection occurs from respiratory failure and cardiovascular collapse, associated with autonomic dysfunction.

Treatment / Management

The treatment of tetanus is based on the severity of the disease. However, all patients must have the following goals of treatment:

1. Early wound debridement
2. Supportive management
3. Antibiotic therapy
4. Early intramuscular or intravenous administration of the human tetanus immunoglobulin (HTIG)
5. Neuromuscular blockade
6. Controlling various manifestations
7. Managing complications

First-line treatment includes HTIG, which removes released tetanospasmin toxin; however, it does not affect the toxin that is already bound to the central nervous system. HTIG also shortens the course of illness and may help in reducing the severity. A dose of 500 U, either intramuscular or intravenous, is as effective as larger doses. HTIG is injected intrathecally, especially in cases of cerebral tetanus. In the case of generalized tetanus, therapeutic doses (3000-6000 U) are also recommended. Debridement of the wound will control the source of toxin production.[15](B3)

Although toxins are the main cause of disease, metronidazole has been shown to slow the progression of the disease. Metronidazole has been shown to decrease mortality, as well.[16] Penicillin, which was used in the past for treatment, is no longer recommended after discovering that it may have synergistic effects with tetanospasmin. Antispasmodics such as benzodiazepines, baclofen, vecuronium, pancuronium, and propofol have been used based on the clinical scenario. Baclofen can also be given intrathecally and is found to be effective in controlling muscle rigidity.[17][18][19](B3)

For more severe tetanus, patients are likely hospitalized in the intensive care unit (ICU) with sedation and mechanical ventilation, which can affect mortality and long-term sequelae. Tracheostomy is preferred because endotracheal tubes may be a stimulus for muscle spasms. Tracheostomy is also indicated in cases where intubation is required for more than 10 days.

Benzodiazepines are considered a cornerstone therapy for tetanus manifestations, and diazepam is the most frequently studied and utilized drug in this regard. It not only reduces anxiety but also causes sedation and relaxes muscles, thereby preventing lethal respiratory complications. Intravenous magnesium has been shown to prevent muscle spasms. Diazepam or midazolam, GABA-agonist benzodiazepines, are given as a continuous infusion to prevent respiratory or cardiovascular complications. To prevent spasms that last more than 5-10 seconds, diazepam should be administered IV, 10-40 mg every 1-8 hours. The dose of midazolam is 5-15 mg/hour IV.

Providers must also provide supportive care, especially for patients with autonomic instability (labile blood pressure, hyperpyrexia, hypothermia). Magnesium is often used in combination with benzodiazepines to manage these complications.[20] It should be given IV in the form of a bolus of 5 g followed by a continuous infusion at a rate of 2-3 g/hour until the spasm control has been achieved.[21] During magnesium infusion, the patellar reflex needs to be monitored; if areflexia develops, the dose should be reduced. Morphine is often used to manage high blood pressure. Beta-blockers can cause hypotension and death. Esmolol in small doses can be used under strict monitoring.(A1)

Providing high-calorie diets to compensate for increased metabolic use from muscle contractions is also important.

Management of respiratory status, cardiovascular complications, and autonomic dysfunction are essential for survival. Moreover, all patients require full tetanus toxoid immunization at recovery; having the infection does not give future immunity.[22][23]

Differential Diagnosis

The only condition that mimics tetanus the most is strychnine poisoning. One of the typical symptoms of tetanus is trismus which may be present in many other conditions. Those conditions are mentioned below:

• Localized infections
• Hysteria
• Neoplasms
• Malignant hyperthermia
• Stimulant drugs
• Acute abdomen
• Dystonic drug effects
• Serotonin syndrome
• Black widow spider envenomation
• Stiff person syndrome

Prognosis

The prognosis after tetanus depends on the time from the first symptom to the first spasm. In general, with a short time to symptom manifestation, the prognosis is poor. The recovery after tetanus is slow and it can take months. Both neonatal and cephalic tetanus have a poor prognosis.

Some patients develop hypotonia and autonomic dysfunction that lasts for months or years. Even those who survive, need tetanus toxoid as the infection does not confer immunity. Usually, patients survive this illness although recovery is slow and some patients may remain hypotonic.

An established scale can be used to predict the prognosis of tetanus. One point is given for each of the following:

• Incubation - shorter than 7 days
• Onset - less than 48 hours
• Causes of tetanus - burns, surgical wounds, septic abortion, umbilical stump, open fractures, or intramuscular injection
• Addiction to opiates
• Generalized tetanus
• Temperature - more than 104 F (40 C)
• Tachycardia - more than 120/min (150/min in neonates)

The total score indicates disease severity:

• 0-1 - mortality of less than 10%
• 2-3 - mortality of 10-20%
• 4 - mortality of 20-40%
• 5-6 - mortality of more than 50%

Complications

Complications include contractions of respiratory muscles, vocal cords, and other critical areas of the body.[24] Sympathetic overactivity is the most significant cause of tetanus-associated mortality in critical patients. Further complications include:

• Vocal cord paralysis leading to respiratory distress
• Autonomic dysfunction- leading to hypertension
• Asphyxia
• Long bone fractures
• Paralytic ileus
• Joint dislocation
• Aspiration pneumonia
• Pressure sores
• Stress ulcers
• Coma
• Nerve palsy
• Urine retention
• Seizures