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% 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 can also result in neonatal tetanus.
Reliable epidemiologic data on worldwide incidence are difficult to obtain, and tetanus is notoriously underreported. Studies have shown that in much of the world only 2–10% of tetanus cases are recorded. Estimates from the early 1980s suggested that tetanus caused >1 million deaths annually. As worldwide vaccination coverage has improved, the number of cases has fallen, particularly among children and neonates, who have been predominantly targeted in recent vaccination programs. In 2006, an estimated 290,000 people died of tetanus, mostly in Southeast Asia and Africa.
The elimination of maternal and neonatal tetanus is one goal of the WHO and its Expanded Programme on Immunization (EPI). An estimated 5% of maternal mortality in the 1990s was attributed to maternal tetanus. Tetanus in pregnant women and neonates is prevented by maternal immunization during pregnancy (see “Prevention,” below), which is an integral component of the EPI. Although immunization coverage continues to increase, maternal and neonatal tetanus still represents an important global health burden, causing ∼180,000 deaths per year.
Tetanus is a rare disease in the developed world. In 2007, a total of 28 cases were reported to the U.S. national surveillance system. Most cases occur in incompletely vaccinated or unvaccinated individuals. Persons >60 years of age are at greater risk of tetanus because antibody levels decrease over time. Injection drug users—particularly those injecting heroin subcutaneously (“skin-popping”)—are increasingly recognized as a high-risk group. Between 1995 and 2000, 15–18% of U.S. tetanus infections occurred in injection drug users. 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.
C. tetani produces two exotoxins: tetanolysin and tetanospasmin. Tetanolysin, which is related to the clostridial toxins and streptolysin, plays no role in the pathogenesis of the disease. Tetanospasmin, generally referred to as “tetanus toxin,” is the neurotoxin that causes the manifestations of disease.
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-motor nerve terminals; evidence suggests binding to both polysialogangliosides and membrane proteins. This binding results in toxin internalization and uptake into the nerves. (Botulinum toxins enter the nervous system by a similar method but remain mostly at the neuromuscular junction and thus produce different clinical features.)
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.