TETANUS

TETANUS

Tetanus is a potentially fatal illness caused by the neurotoxin produced by the spore-bearing anaerobic bacterium Clostridium tetani. As the causative organism and its spores are ubiquitous, nonimmune individuals in any part of the world may get tetanus unless they are protected by the highly effective vaccine.

Epidemiology

As a result of effective universal immunization, tetanus is rare in the developed world. Twenty to 40 cases of tetanus occur annually in the United States and 12 to 15 cases per year have been reported from the United Kingdom in the last 10 years. Although progressively declining in the developing world due to improved immunization coverage, according to WHO figures, more than 500 cases were reported in 2012 from each of these nations: Angola, Bangladesh, Congo, India, and Uganda. While tetanus may affect individuals of all ages, a significant number of cases in developed countries are elderly people who did not receive a primary immunization or lacked the booster dosage needed to maintain protective immunity. In developing countries, most cases are neonates (tetanus neonatorum), children who are born to nonimmunized mothers and thus lack transplacentally acquired passive immunity. Infection of the umbilical stump due to poor hygiene results in severe tetanus that has mortality in excess of 60%.

The infection is caused by the gram-positive, spore-bearing bacterium C. tetani, the spores of which exist in the soil, in animal feces, and even in the human gastrointestinal tract. Spores remain dormant and viable for several months and are destroyed by autoclaving at 1 atmosphere pressure at 120°C for 15 minutes. When inoculated into human or animal tissues, they transform into motile bacilli in an anerobic environment that produce a potent exotoxin, tetanospasmin, which produces the manifestations of tetanus. It must be emphasized that tetanus is not transmitted from human to human, and patients do not require isolation.

Risk Factors

Elderly individuals are at increased risk, as they may not have received adequate immunization or may have waning immunity. Other predisposed groups include immigrants from countries with an unreliable immunization program, immunosuppressed individuals (with HIV infection or receiving immunosuppressive drugs), and intravenous drug addicts. Local factors include wounds with crushed, devitalized tissue or contaminated by dirt or rust, such as open fractures, punctures, and abscesses. However, even scratches, chronic ulcers, or tattooing may cause tetanus. In developing countries, unsafe practices related to termination of pregnancy may cause maternal tetanus; newborn babies born outside of medical facilities are at risk of neonatal tetanus.

Pathophysiology

Tetanospasmin is a highly toxic protein released by C. tetani. It is absorbed into the circulation and reaches the ends of motor axons all over the body, from where it is transported proximally along the axonal cytoplasm to motor nuclei in the brainstem and spinal cord at a rate of 3 to 13 mm/hour. A fragment of the toxin then binds inhibitory interneurons that produce gamma-amino butyric acid (GABA) and glycine and inactivates synaptobrevin, a protein that is essential for the release of these neurotransmitters from presynaptic vesicles.

The loss of normal inhibition at motor and autonomic neurons results in spontaneous discharge of nerve impulses as well as exaggerated responses to stimuli manifesting as tonic muscle contraction with superadded intermittent muscle spasms. As tetanospasmin reaches the motor nuclei of the shortest motor axons first, muscles innervated by motor cranial nerves are affected first, followed by trunk muscles, and finally the extremities. Autonomic overactivity results in severe tachycardia, swings in blood pressure, profuse sweating, and (rarely) ileus. An exaggerated startle-like response to stimuli with motor and autonomic components is also typical. Generalized spasms may mimic tonic seizures.

Clinical Manifestations

An attempt should be made to locate the predisposing wound, such as cuts, abrasions, burns, puncture wounds, and other skin lesions.

Uncommon causes include needle-sticks in intravenous drug abusers, ulcerated malignant tumors, and chronic middle-ear infection in children (otogenic tetanus). In up to 30% of patients, no site of infection is discovered. The incubation period is the interval between the injury and the onset of symptoms and can range from a few days to a few months (usually 3–21 days). A short incubation period (< 7 days) suggests the likelihood of developing severe tetanus; however, a long incubation period does not necessarily indicate a milder disease. The period of onset (the interval between the first symptom and first paroxysmal muscle spasm) is a better predictor of severity: early elective tracheal intubation and mechanical ventilation are usually required if the interval is < 48 hours.

Generalized Tetanus

Initial symptoms include an inability to open the mouth (lockjaw or trismus), difficulty in chewing and swallowing, and stiffness of neck muscles. The contraction of facial muscles produces the characteristic sneering smile (risus sardonicus) (Figure 1). In severe cases, intermittent spasms are provoked by attempts to speak or swallow.

Pooled saliva from hypersalivation and dysphagia may trigger cough and laryngeal spasms; if prolonged, these may prove fatal. Rigidity of paraspinal muscles follows, and hyperextension of the spine results in opisthotonus (Figure 2). Finally, proximal muscles of the extremity are also affected. Deep tendon reflexes are always exaggerated and ankle clonus is common. Tonic muscle spasms may affect head and neck muscles and laryngeal muscles, or may be generalized. Paroxysmal spasms occur spontaneously or in response to loud noise, bright lights, or attempts to speak or swallow. Prolonged spasms may compromise breathing.

FIGURE 1    Typical facial expression with the sneering smile  (risus sardonicus), wrinkled forehead, narrow palpebral fissures, and “crow’s feet” at the lateral palpebral margins from the tonic contraction of muscles of facial expression in moderate  tetanus.

FIGURE 2    Spasm of paraspinal muscles, producing  the hyperextended opisthotonic posture in severe  tetanus.

The Ablett classification is commonly used to grade the severity of tetanus. Grade I (mild) tetanus is characterized by moderate trismus and general spasticity without spasms, dysphagia, or respiratory distress. Grade II (moderate) tetanus has severe trismus, intermittent short spasms, mild tachypnea, and dysphagia. Grade III (severe) tetanus is associated with severe rigidity, prolonged spasms, severe dysphagia, tachypnea, apneic spells, and tachycardia. The presence of additional violent autonomic disturbances with persistent or intermittent episodes of severe hypertension and tachycardia alternating with hypotension and bradycardia is classified as Grade IV (very severe) tetanus. Cardiac arrhythmias, peripheral vasoconstriction, and sudden asystole may also occur in very severe tetanus.

Despite the use of antitetanus immune globulin (HyperTET) to neutralize circulating tetanus toxin, the disease may progress for up to 2 weeks as more intraaxonal toxin continues to reach the central nervous system. Manifestations persist for another 2 to 3 weeks before gradually subsiding. During this period, an apparently stable patient is at risk of developing sudden asphyxia due to severe generalized or laryngeal spasms. Patients may develop fever, rhabodomyolysis, and hyperthermia due to excessive muscular activity.

Cephalic Tetanus

Following injuries to the head or face, in some patients, the toxin reaches the local motor nuclei earlier and produces a combination of partial paralysis and overactivity—more severely affected motor neurons stop functioning while the remaining fibers are overactive and cause muscle spasm (Figure 3).

FIGURE 3    Cephalic tetanus: This 6-year-old child developed  mild tetanus 3 weeks after a wound on his right cheek was sutured. He had cephalic tetanus characterized by partial paralysis of the right  facial nerve along with overactivity of the unaffected nerve fibers. A, Note the overactivity of the facial muscles with a narrow palpebral and prominent nasolabial fold on the same side as the injury. On asking him to  shut his eyes tight (B), weakness of the orbicularis oculi and other facial muscles on the right side become  manifest.

Localized Tetanus

In this rare form of tetanus, manifestations are restricted to muscles in the region of the wound. These patients have a good prognosis.

Diagnosis

C. tetani can be isolated from the wound in < 30% of cases, and microbiological and other laboratory tests do not help in confirming the diagnosis. The diagnosis is entirely clinical. In an individual with a predisposing injury, the presence of trismus, rigidity of neck, abdominal and paraspinal muscles, and severe hyperreflexia are suggestive. The spatula test is a useful bedside test: A spatula (tongue depressor) is inserted into the mouth to touch the posterior pharyngeal wall. Normally, a gag reflex is activated in an attempt to expel the spatula. In tetanus, severe spasms of the masseters results in the patient biting on the spatula, making it difficult to withdraw—a positive test. In one study, the spatula test was positive in 94% of patients with tetanus and in none without tetanus. The electromyogram shows the continuous discharge of motor units in moderate tetanus and the absence of the normal silent period.

Differential Diagnosis

While the diagnosis of tetanus is easy in severe tetanus, it may be mistaken for other conditions in its initial stages (Table 1). The spatula test is negative in other conditions causing trismus. Abdominal muscles usually relax after adequate sedation. As in spasticity due to cord compression, deep reflexes are exaggerated; however, the plantar response, which is extensor in spinal cord disorders, is always flexor with tetanus. Unlike seizures or other intracranial diseases, the patient with tetanus is always fully alert and awake.

Table 1

Conditions that Mimic Clinical Manifestations of Tetanus

Clinical

Feature           Differential Diagnosis

Trismus Acute tonsillar abscess, temporomandibular joint disease, extraptramidal reaction to drugs, dental pathology
Neck stiffness Cervical spine disease; extrapyramidal reaction to drugs such as antipsychotics, antiemetics, or metoclopramide;  meningitis;  subarachnoid hemorrhage
Abdominal rigidity Acute abdomen
Dysphagia Myasthenia gravis, acute bulbar paralysis, rabies
Muscle spasms Seizures, spasticity due to spinal cord disease, stiff man syndrome

Treatment

In patients with life-threatening spasms, prompt, adequate sedation is the first step in management. Patients must be observed in an intensive care unit because the disease may rapidly worsen. They should be nursed in a quiet, dimly lit room in order to keep external stimuli to a minimum—this is difficult in modern intensive care units.

Neutralization of Toxin

Although unsupported by randomized studies, human tetanus immune globulin (HyperTET) (3000–6000 units) is administered intramuscularly to neutralize the circulating toxin. This does not bind to the toxin that has already entered neurons. There is insufficient evidence favoring intrathecal administration1 of tetanus immune globulin over the usual intramuscular route, although one randomized study showed a shortening of the course of tetanus.

Equine antiserum2 (10,000–20,000 units) may be administered after skin testing for hypersensitivity. Though rarely used today due to the risk of anaphylaxis or serum sickness, it has the advantage of being administered intravenously.

Control of Clostridial Infection

Benzylpenicillin (Penicillin G) in a dose of 10 to 12 million units per day is given intravenously for 10 days. In one study, metronidazole (Flagyl) (500 mg every 6 hour for 10 days) was superior to procaine penicillin (Wycillin),1 presumably because procaine and penicillin are GABA antagonists and may worsen manifestations of tetanus.

However, a more recent study showed that a single intramuscular injection of 1.2 million units of benzathine penicillin (Bicillin LA)1 was as effective as benzylpenicillin or metronidazole. Fortunately, resistance to these antibiotics has not been reported. Debridement of the infected wound and abscess drainage should be performed after spasms have been adequately controlled.

Control of Muscle Spasms

Benzodiazepines (diazepam [Valium] or lorazepam [Ativan]1) are the preferred drugs and act by enhancing the effect of GABA on its receptor on the postsynaptic membrane, thus potentially antagonizing the effect of tetanospasmin. However, as very little GABA is released in tetanus, large doses (up to 1000 mg/day3) of diazepam may be required to achieve adequate sedation and muscle relaxation.

Diazepam may be administered intravenously (10–30 mg in 5 mg boluses every 5 minutes)3 or through a nasogastric tube (10–40 mg every 1 to 2 hours).3 Barbiturates and chlorpromazine (Thorazine)1 are alternative agents. Other sedative hypnotic agents such as midazolam (Versed)1 and propofol (Diprivan)1 have also been used with good effect. In mild to moderate tetanus, drug doses can be titrated to achieve moderate sedation and control rigidity and spasms without causing respiratory depression. In severe cases, however, spasms may not be controlled despite large doses, increasing the risk of severe central nervous system (CNS) depression. In these patients, heavy sedation combined with neuromuscular blockade and mechanical ventilation is required. In about 10% of cases, benzodiazepines may produce paradoxical excitation instead of sedation; increasing doses make the patient more wakeful, agitated, and delirious, with increased spasms. Discontinuation of diazepam and the use of barbiturates and chlorpromazine may prevent the need for paralysis and mechanical ventilation. Pancuronium (Pavulon),1 vecuronium (Norcuron),1 and rocuronium (Zemuron)1 are often used for neuromuscular blockade. Atracurium (Tracrium)1 could also be used but may have unfavorable cardiovascular effects. Intravenous and intrathecal baclofen (Lioresal Intrathecal)1 have been used in some case.

Airway Management

Tracheostomy or endotracheal intubation is required in moderate and severe tetanus to prevent respiratory failure due to laryngeal spasm and aspiration of oropharyngeal secretions. In most developing countries, elective tracheostomy is performed early in severe tetanus. In countries with superior intensive care facilities, heavy sedation, neuromuscular blockade, endotracheal intubation, and mechanical ventilation are preferred, with tracheostomy being reserved for those who need prolonged ventilation.

Control of Autonomic Disturbances

With good intensive care, mortality due to respiratory failure has been drastically reduced. Autonomic dysfunction is now the major challenge in patients with severe tetanus; it is common even in sedated and paralyzed patients. Various measures to control autonomic fluctuations include intravenous fluid loading, oral and parenteral beta-blockers, alpha-blockers, centrally acting sympatholytics such as clonidine (Catapres)1 or dexmedetomidine (Precedex),1 and epidural or spinal bupivacaine (Marcaine).1 More recently, infusion of dexmedetomidine has been used by some authors. Many patients may develop sudden asystole, possibly due to sudden parasympathetic discharge, catecholamine-induced myocardial damage, or sudden loss of sympathetic drive.

Consequently, the use of long-acting antiadrenergic drugs should be avoided. Increasing the level of sedation itself is also effective, to a significant extent.

The agent most frequently used for autonomic dysfunction is intravenous magnesium sulfate.1 A randomized controlled trial in Vietnamese patients showed that magnesium sulfate did not decrease mortality, ICU stay, or the need for mechanical ventilation but did reduce the dose of sedatives and neuromuscular blocking drugs required. This study used a loading dose of 40 mg/kg over 30 minutes, followed by intravenous infusion of 2 g/hour in patients > 45 kg and 1 to 5 g/hour in patients ≤ 45 kg. Infusion was titrated to maintain serum magnesium levels between 2 and 4 mmol/L.

Other Measures

Continuous muscle hyperactivity and spasms greatly increase caloric requirements. Most patients require nasogastric tube feeding because of trismus and dysphagia. A catabolic state similar to sepsis may develop in very severe tetanus. Consequently, patients lose up to 15% of their body weight during the illness. Good nursing care is essential to prevent pressure sores, deep vein thrombosis, stress ulcers, and aspiration pneumonia. Urinary catheterization is required in most patients as urinary retention is common and distension of the urinary bladder may provoke spasms and autonomic overactivity. All patients should be started on a primary immunization schedule against tetanus.

Complications

Respiratory failure may occur due to laryngeal obstruction, prolonged spasm of respiratory muscles, aspiration pneumonia, or sedative drugs. Severe spasms may result in tongue-bite, compression fractures of midthoracic vertebrae, rhabdomyolysis, myoglobinuria, and renal failure. Rarely, patients may develop acute respiratory distress syndrome (ARDS) either due to tetanus itself or as a result of secondary bacterial sepsis. Cardiac arrhythmias and sudden asystole are common in patients with autonomic dysfunction. Acute myocardial infarction may occur in elderly patients with underlying coronary artery disease due to sympathetic overactivity. Deep vein thrombosis and pressure sores are preventable complications. The overall mortality ranges from 40% to 60% in countries with inadequate health care facilities. With good intensive care, mortality as low as 10% is reported in some series. Mortality is higher in neonates, the elderly, and patients with a short incubation period and period of onset.

Prevention

Adsorbed tetanus toxoid (Tt), derived from formaldehyde-treated tetanus toxin, is extremely effective in inducing active immunity. It is available as a single-antigen preparation or in combination with diphtheria toxoid as pediatric diphtheria-tetanus toxoid (DT) or adult tetanus-diphtheria (Td), and with both diphtheria toxoid and acellular pertussis vaccine as DTaP (Infanrix, Tripedia) or Tdap (Adacel, Boostrix) (lower-case alphabets indicate lower doses of antigens).

Pediatric vaccines (DT and DTaP) contain identical amounts of tetanus toxoid as adult vaccines, but three to four times as much diphtheria toxoid. The usual schedule for primary immunization in children < 7 years consists of four doses of DTaP or DT at age 2, 4, 6, and 15 to 18 months. A booster dose is recommended at 4 to 6 years of age. In individuals aged 7 years or older, three doses of the adult formulation are administered; the second dose is given 4 to 8 weeks after the first, and the third dose after another 4 to 6 months. Further booster doses are needed every 10 years to maintain antibody titers above the protective level of 0.1 IU/mL.

After administration of Tt to individuals with wounds, protective titers of antibody are achieved after at least 2 weeks. Consequently, passive immunization with 250 units of human tetanus immune globulin (HyperTET) or 1500 units of equine antitetanus serum2 administered intramuscularly is needed to confer protection during these initial few weeks. This is especially required in individuals with tetanus-prone wounds who have not received at least three doses of tetanus toxoid in the past. Previously unimmunized individuals with clean, minor, nontetanus prone wounds do not need any passive immunization, but should receive active immunization. Passive immunization is not necessary in those who have received three or more doses of the toxoid. These individuals should receive a dose of Tt (or Td) if more than 10 years have elapsed since the last booster dose and they have nontetanus prone wounds or if > 5 years have elapsed after the booster dose and they have a tetanus-prone wound.

In countries where neonatal tetanus is common, primary immunization of women during pregnancy has been advocated as a public health program to prevent neonatal tetanus.

References

1.     Apte N.M., Karnad D.R. The spatula test: A simple bedside test to diagnose tetanus. Am J Trop Med Hyg. 1995;53:386–387.

2.    Centers for Disease Control and Prevention. In: Atkinson W., Wolfe S., Hamborsky J., eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. ed 12th Washington, DC: Department of Health and Human Services, Centers for Disease Control and Prevention; 2011:291–299.

3.     Farrar J.J., Yen L.M., Cook T., et al. Tetanus. J Neurol Neurosurg Psychiatry. 2000;69:292–301.

4.    Gibson K., Uwineza J.B., Kiviri W., Parlow J. Tetanus in developing countries: A case series and review. Can J Anaesth. 2009;56:307–315.

5.     Lisboa T., Ho Y.L., Filho G.T.H., et al. Guidelines for the management of accidental tetanus in adult patients. Rev Bras Ter Intensiva. 2011;23:394–409.

6.      Rodrigo C., Samarakoon L., Fernando S.D., Rajapakse S. A meta- analysis of magnesium for tetanus. Anaesthesia. 2012;67:1370– 1374.

7.    Roper M.H., Vandelaer J.H., Gasse F.L. Maternal and neonatal tetanus. Lancet. 2007;370:1947–1959.

8.    Thwaites C.L., Yen L.M., Loan H.T., et al. Magnesium sulphate for treatment of severe tetanus: A randomized controlled trial. Lancet. 2006;368:1436–1443.

9.       Trujillo M.H., Castillo A., Espana J., et al. Impact of intensive care management on the prognosis of tetanus. Analysis of 641 cases. Chest. 1987;92:63–65.

1  Not FDA approved for this  indication.

2  Not available in the United  States.

3  Exceeds dosage recommended by the  manufacturer.

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