CHAPTER 49: TETANUS

Tetanus is an acute disease manifested by skeletal muscle spasm and autonomic nervous system disturbance. It is caused by a powerful neurotoxin produced by the bacterium Clostridium tetani and is completely preventable by vaccination. C. tetani is found throughout the world, and tetanus commonly occurs where the vaccination coverage rate is low. In developed countries, the disease is seen occasionally in individuals who are incompletely vaccinated. In any setting, established tetanus is a severe disease with a high mortality rate.

Tetanus is diagnosed on clinical grounds (sometimes with supportive laboratory confirmation of the presence of C. tetani; see “Diagnosis,” below), and case definitions are often used to facilitate clinical and epidemiologic assessments. The Centers for Disease Control and Prevention (CDC) defines tetanus as “the acute onset of hypertonia or … painful muscular contractions (usually of the muscles of the jaw and neck) and generalized muscle spasms without other apparent medical cause.” Neonatal tetanus is defined by the World Health Organization (WHO) as “an illness occurring in a child who has the normal ability to suck and cry in the first 2 days of life but who loses this ability between days 3 and 28 of life and becomes rigid and has spasms.” Given the unique presentation of neonatal tetanus, the history generally permits accurate classification of the illness with a high degree of probability. Maternal tetanus is defined by the WHO as tetanus occurring during pregnancy or within 6 weeks after the conclusion of pregnancy (whether with birth, miscarriage, or abortion).

C. tetani is an anaerobic, gram-positive, spore-forming rod whose spores are highly resilient and can survive readily in the environment throughout the world. Spores resist boiling and many disinfectants. In addition, C. tetani spores and bacilli survive in the intestinal systems of many animals, and fecal carriage is common. The spores or bacteria enter the body through abrasions, wounds, or (in the case of neonates) the umbilical stump. Once in a suitable anaerobic environment, the organisms grow, multiply, and release tetanus toxin, an exotoxin that enters the nervous system and causes disease. Very low concentrations of this highly potent toxin can result in tetanus (minimum lethal human dose, 2.5 ng/kg).

In 20–30% of cases of tetanus, no puncture entry wound is found. Superficial abrasions to the limbs are the commonest infection sites in adults. Deeper infections (e.g., attributable to open fracture, abortion, or drug injection) are associated with more severe disease and worse outcomes. In neonates, infection of the umbilical stump can result from inadequate umbilical cord care; in some cultures, for example, the cord is cut with grass or animal dung is applied to the stump. Circumcision or ear-piercing also can result in neonatal tetanus.

Tetanus is a rare disease in the developed world. Two cases of neonatal tetanus have occurred in the United States since 1989. Between 2001 and 2008, a total of 231 cases of tetanus were reported to the U.S. national surveillance system. Most cases occur in incompletely vaccinated or unvaccinated individuals. Vaccination status is known in 50% of cases reported in the United States between 1972 and 2009; among these cases, only 16% of patients had had three or more doses of tetanus toxoid.

Persons >60 years of age are at greater risk of tetanus because antibody levels decrease over time. One-third of recent cases in the United States were in persons >65 years old. Injection drug users—particularly those injecting heroin subcutaneously (“skin-popping”)—are increasingly recognized as a high-risk group (15% of all cases in 2001–2008). In 2004, an outbreak of tetanus occurred in the United Kingdom, which had previously reported low rates among drug users. The reasons for this outbreak remain unclear but are thought to involve a combination of heroin contamination, skin-popping, and incomplete vaccination. Since then, only seven sporadic cases have been reported in the United Kingdom.

Genome sequencing of C. tetani has allowed identification of several exotoxins and virulence factors. Only those bacteria producing tetanus toxin (tetanospasmin) can cause tetanus. Although closely related to the botulinum toxins in structure and mode of action, tetanus toxin undergoes retrograde transport into the central nervous system and thus produces clinical effects different from those caused by the botulinum toxins, which remain at the neuromuscular junction.

Toxin is transported by intra-axonal transport to motor nuclei of the cranial nerves or ventral horns of the spinal cord. Tetanus toxin is produced as a single 150-kDa protein that is cleaved to produce heavy (100-kDa) and light (50-kDa) chains linked by a disulfide bond and noncovalent forces. The carboxy terminal of the heavy chain binds to specific membrane components in presynaptic α-motor nerve terminals; evidence suggests binding to both polysialogangliosides and membrane proteins. This binding results in toxin internalization and uptake into the nerves. Once inside the neuron, the toxin enters a retrograde transport pathway, whereby it is transported proximally to the motor neuron body in what appears to be a highly specific process. Unlike other components of the endosomal contents, which undergo acidification following internalization, tetanus toxin is transported in a carefully regulated pH-neutral environment that prevents an acid-induced conformational change that would result in light-chain expulsion into the surrounding cytosol.

The next stage in toxin trafficking is less clearly understood but involves tetanus toxin’s escaping normal lysosomal degradation processes and undergoing translocation across the synapse to the GABA-ergic presynaptic inhibitory interneuron terminals. Here the light chain, which is a zinc-dependent endopeptidase, cleaves vesicle-associated membrane protein 2 (VAMP2, also known as synaptobrevin). This molecule is necessary for presynaptic binding and release of neurotransmitter; thus tetanus toxin prevents transmitter release and effectively blocks inhibitory interneuron discharge. The result is unregulated activity in the motor nervous system. Similar activity in the autonomic system accounts for the characteristic features of skeletal muscle spasm and autonomic system disturbance. The increased circulating catecholamine levels in severe tetanus are associated with cardiovascular complications.

Relatively little is known about the processes of recovery from tetanus. Recovery can take several weeks. Peripheral nerve sprouting is involved in recovery from botulism, and similar central nervous system sprouting may occur in tetanus. Other evidence suggests toxin degradation as a mechanism of recovery.

Tetanus produces a wide spectrum of clinical features that are broadly divided into generalized (including neonatal) and local. In the usually mild form of local tetanus, only isolated areas of the body are affected and only small areas of local muscle spasm may be apparent. If the cranial nerves are involved in localized cephalic tetanus, the pharyngeal or laryngeal muscles may spasm, with consequent aspiration or airway obstruction, and the prognosis may be poor. In the typical progression of generalized tetanus (Fig. 49-1), muscles of the face and jaw often are affected first, presumably because of the shorter distances toxin must travel up motor nerves to reach presynaptic terminals. Neonates typically present with inability to suck.

In assessing prognosis, the speed at which tetanus develops is important. The incubation period (time from wound to first symptom) and the period of onset (time from first symptom to first generalized spasm) are of particular significance; shorter times are associated with worse outcome. In neonatal tetanus, the younger the infant is when symptoms occur, the worse the prognosis.

The commonest initial symptoms are trismus (lockjaw), muscle pain and stiffness, back pain, and difficulty swallowing. In neonates, difficulty in feeding is the usual presentation. As the disease progresses, muscle spasm develops. Generalized muscle spasm can be very painful. Commonly, the laryngeal muscles are involved early or even in isolation. This is a life-threatening event as complete airway obstruction may ensue. Spasm of the respiratory muscles results in respiratory failure. Without ventilatory support, respiratory failure is the commonest cause of death in tetanus. Spasms strong enough to produce tendon avulsions and crush fractures have been reported, but this outcome is rare.

Autonomic disturbance is maximal during the second week of severe tetanus, and death due to cardiovascular events becomes the major risk. Blood pressure is usually labile, with rapid fluctuations from high to low accompanied by tachycardia. Episodes of bradycardia and heart block can also occur. Autonomic involvement is evidenced by gastrointestinal stasis, sweating, increased tracheal secretions, and acute (often high-output) renal failure.

The diagnosis of tetanus is based on clinical findings. As stated above, treatment should not be delayed while laboratory tests are conducted. Culture of C. tetani from a wound provides supportive evidence. Serum anti-tetanus immunoglobulin G may also be measured in a sample taken before the administration of antitoxin or immunoglobulin. Serum levels >0.1 IU/mL are deemed protective and do not support the diagnosis of tetanus. If levels are below this threshold, a bioassay for serum tetanus toxin may be helpful, but a negative result does not exclude the diagnosis. Polymerase chain reaction also has been used for detection of tetanus toxin, but its sensitivity is unknown.

The few conditions that mimic generalized tetanus include strychnine poisoning and dystonic reactions to antidopaminergic drugs. Abdominal muscle rigidity is characteristically continuous in tetanus but is episodic in the latter two conditions. Cephalic tetanus can be confused with other causes of trismus, such as oropharyngeal infection. Hypocalcemia and meningoencephalitis are included in the differential diagnosis of neonatal tetanus.

Rapid development of tetanus is associated with more severe disease and poorer outcome; it is important to note time of onset and length of incubation period. More sophisticated modeling has revealed other important predictors of prognosis (Table 49-1). Few studies have formally addressed long-term outcomes of tetanus. However, it is generally accepted that recovery is typically complete unless periods of hypoventilation have been prolonged or other complications have ensued. Studies of children and neonates have suggested a higher incidence of neurologic sequelae. Neonates may be at increased risk of learning disabilities, behavioral problems, cerebral palsy, and deafness.

Tetanus is prevented by good wound care and immunization (Chap. 5). In neonates, use of safe, clean delivery and cord-care practices as well as maternal vaccination are essential. The WHO guidelines for tetanus vaccination consist of a primary course of three doses in infancy, boosters at 4–7 and 12–15 years of age, and one booster in adulthood. In the United States, the CDC suggests an additional dose at 14–16 months and boosters every 10 years. “Catch-up” schedules recommend a three-dose primary course for unimmunized adolescents followed by two further doses. For persons who have received a complete primary course in childhood but no further boosters, two doses at least 4 weeks apart are recommended.

Standard WHO recommendations for prevention of maternal and neonatal tetanus call for administration of two doses of tetanus toxoid at least 4 weeks apart to previously unimmunized pregnant women. However, in high-risk areas, a more intensive approach has been successful, with all women of childbearing age receiving a primary course along with education on safe delivery and postnatal practices.

Individuals sustaining tetanus-prone wounds should be immunized if their vaccination status is incomplete or unknown or if their last booster was given >10 years earlier. Patients sustaining wounds not classified as clean or minor should also undergo passive immunization with TIG. It is recommended that tetanus toxoid be given in conjunction with diphtheria toxoid in a preparation with or without acellular pertussis: DTaP for children <7 years old, Td for 7- to 9-year olds, and Tdap for children >9 years old and adults.

In the early 1980s, tetanus caused more than 1 million deaths a year, accounting for an estimated 5% of maternal deaths and 14% of all neonatal deaths. In 1989, the World Health Assembly adopted a resolution to eliminate neonatal tetanus by the year 2000; elimination was defined as <1 case/1000 live births in every district in every country. By 1999, elimination was still to be achieved in 57 countries and the deadline was extended until 2005, with the additional target of eliminating maternal tetanus (tetanus occurring during pregnancy or within 6 weeks of its end). Ratification of the Millennium Development Goals, in particular goal 4 (achieving a two-thirds reduction in the mortality rate among children under 5 by 2015), has further focused attention on reducing deaths from vaccine-preventable disease, particularly in the first 4 weeks of life.

Because vaccination reduces the incidence of neonatal tetanus by an estimated 94%, immunization of pregnant women with two doses of tetanus toxoid at least 4 weeks apart has been the primary method of maternal and neonatal tetanus elimination. In some areas, all women of childbearing age have been targeted as a means of increasing vaccination coverage. In addition, educational programs have focused on improving hygiene during the birth process, an intervention that in itself is estimated to reduce neonatal tetanus deaths by up to 40%.

The latest available data show that 34 countries have yet to eliminate maternal and neonatal tetanus, although incidence has declined significantly. Worldwide, deaths from neonatal tetanus fell by 92% between 1990 and 2008; in the latter year, with 84% of newborns protected from the disease by maternal vaccination, there were an estimated 59,000 neonatal tetanus deaths. Despite this relative success, immunization programs need to be ongoing as there is no tetanus herd immunity effect and C. tetani contamination of soil and feces is widespread.