Tetanus

• 1. Introduction

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  Tetanus, better known as lockjaw, can lock the muscles so violently that the body breaks its own bones. The bacterium Clostridium tetani causes it, and the illness does not pass from one person to another. Even so, about 10% of those who contract it die. Recovery for the survivors can stretch across months. The organism itself is humble, a microbe that rides on everyday soil and dust until a wound gives it a way in. How does a single injury set off weeks of spasms? Why does the rusty nail carry the blame? And why does surviving the disease usually leave no protection behind?

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• 2. Rust, Soil and Spores

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  Horses, sheep, cattle, dogs, cats, rats, guinea pigs and chickens all carry C. tetani in their intestines, and their droppings spread it widely. That is why soil treated with manure may hold spores, and why farming regions can be risky. In agricultural areas, a significant number of adults may harbor the organism themselves. The disease turns up in every part of the world, but it is most frequent in hot, wet climates where the soil is rich in organic matter. Spores have also been found on the skin and in contaminated heroin.

  The rusty nail is the best-known suspect, yet rust itself does not cause tetanus. Rusty objects simply tend to lie outdoors, where soil bacteria are common. Their rough surface also traps dirt in tiny crevices, and the nail drives that dirt deep beneath the skin. A clean nail that punctures a foot carries the same danger. Believing that rust is the culprit, or that a rust-free puncture is safe, is a common misconception.

  In a puncture wound, oxygen is scarce, and C. tetani is an anaerobic bacterium. Its endospore is a dormant survival structure that wakes and begins to metabolize once it lands somewhere suitable. The low-oxygen pocket under the skin is exactly such a place. Less often, tetanus follows surgery, intramuscular injections, compound fractures or dental infections. Animal bites can transmit it too.

  Goats and sheep are the animals in which tetanus is found most often. Affected animals walk with a stiff, abnormal gait, hold the head and neck out, and carry a rigid, straight tail. The back arches, the jaw stiffens, the eyelids droop, and eating and drinking become difficult. Some die of asphyxiation when the breathing muscles are paralyzed. Whatever the host, the spore that starts it all is shaped like a turkey drumstick, and a change in oxygen levels lets it spread quickly.

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• 3. The Toxin's Long Climb

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  Tetanospasmin is the toxin that does the damage, and it is built from a heavy chain and a light chain arranged in three domains. The heavy chain has two of them. One end helps the toxin pass through membranes, while the other end finds the right receptor on the right neuron. The light chain carries the enzyme that does the cutting.

  From the wound, the toxin reaches the neuromuscular junction by way of the bloodstream and attaches to the membrane of a motor neuron. There the heavy chain recognizes particular glycoproteins and glycolipids. The neuron swallows the toxin inside a vesicle, which travels back along the axon, past the cell body and down the dendrites. At the end of that route lies the central nervous system. The toxin is released into the gap between cells and attaches to inhibitory neurons in much the same way.

  On its second entry, the toxin is swallowed inside an acidic vesicle. Scientists do not fully understand how, but the firing of the inhibitory neuron seems to pull the toxin in. Once inside, the low pH changes the toxin from a water-soluble form to a hydrophobic one. With those oily patches exposed, it slips into the vesicle wall and forms an ion channel that lets Na+, K+, Ca2+ and Cl- through without discrimination. Experts agree this channel is involved in moving the light chain into the cell fluid, but not on how. One proposal says the unfolded chain leaves through the pore. Another says the ion flow bursts the vesicle.

  Free in the cell fluid, the light chain acts as a zinc-dependent protease and attacks a protein called VAMP, also known as synaptobrevin. It cuts between the positions Gln76 and Phe77. VAMP is needed for vesicles to fuse with the membrane, so the neurotransmitters GABA and glycine can no longer be released. Those two chemicals normally restrain motor neurons and help muscles relax after contracting. Without them, motor neurons fire out of control, and the result is spasm and spastic paralysis.

  The zinc motif His-Glu-Xaa-Xaa-His in the light chain was long only a hypothesis for how the cut was made. Experiment later confirmed it. Stripping all zinc from the neuron with heavy metal chelators inhibited the toxin, and adding zinc back reactivated it.

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• 4. Four Forms

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  About 80% of cases are generalized tetanus, and it moves downward through the body. Lockjaw comes first, then facial spasms that pull the face into an expression called risus sardonicus. Next come a stiff neck, trouble swallowing, and rigidity in the chest and calf muscles. The back can arch into the posture known as opisthotonos. Fever, sweating, raised blood pressure and bursts of rapid heartbeat accompany all of this. When the muscles used for breathing are caught, breathing problems follow.

  The incubation period is usually about ten days, though it can run to several months. The farther the injury sits from the central nervous system, the longer the wait. A shorter wait signals more severe symptoms. The death rate is higher in unvaccinated people and in those over 60 years of age.

  Neonatal tetanus, called trismus nascentium, strikes newborns, usually 4-14 days after birth and averaging about 7. It most often enters through an unhealed umbilical stump, especially one cut with a non-sterile instrument. Babies born to vaccinated mothers are shielded by passive immunity.

  Local tetanus is uncommon and milder, killing only about 1% of patients. The muscles contract persistently in the same area as the injury, sometimes for many weeks before easing. It can also be the warning that generalized disease is coming.

  Cephalic tetanus is the rarest form, at 0.9-3% of cases, and it stays confined to the muscles and nerves of the head. It follows trauma such as a skull fracture, laceration, eye injury, dental extraction or otitis media. Paralysis of the facial nerve is most often involved, bringing lockjaw, facial palsy or a drooping eyelid. If it progresses to the generalized form, the case fatality rate is 15-30%. Because it is so rare, clinicians may not even suspect tetanus when it appears.

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• 5. Reading the Signs

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  In only 30% of cases can the bacterium be recovered from the wound, so diagnosis cannot depend on finding it. No blood test exists for tetanus. Doctors rely on the symptoms they see. C. tetani can even be isolated from people who do not have the disease. In the laboratory, the organism is identified only by showing that it produces tetanospasmin in mice.

  The spatula test offers a bedside shortcut. A clinician touches the back wall of the throat with a soft-tipped instrument. A healthy person gags, trying to expel the object. A person with tetanus clamps the jaw down on the spatula instead. A short report in The American Journal of Tropical Medicine and Hygiene described a study in which the test produced no false positives, and 94% of infected people tested positive.

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• 6. Intensive Care

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  Mild tetanus is treated with tetanus immunoglobulin, also called tetanus antitoxin, given by vein or by injection into a muscle. Intravenous metronidazole is the preferred antibiotic, used to reduce toxin production. Benzodiazepines such as diazepam and lorazepam control the spasms. The wound itself is cleaned and any dead tissue removed.

  Severe cases are admitted to intensive care. One option is an intrathecal injection of human tetanus immunoglobulin, which raises clinical improvement from 4% to 35%. A tracheotomy secures the airway, because an endotracheal tube is itself a stimulus for spasm. Mechanical ventilation then continues for 3 to 4 weeks. Magnesium sulfate by infusion and a continuous diazepam drip help control spasms and autonomic dysfunction. In extreme cases, the patient is paralyzed with curare-like drugs.

  Labetalol, magnesium, clonidine or nifedipine may be needed during severe tetanus. The reason is the autonomic effects, which swing blood pressure between high and low and body temperature between fever and chill.

  Between 3500 and 4000 calories and at least 150 g of protein a day is the nutrition target, because constant muscle activity strains the metabolism. It is given as liquid through a tube into the stomach or through a drip into a vein. Full recovery takes 4 to 6 weeks, since the body must regenerate destroyed nerve axon terminals.

  Metronidazole can be given by vein, by mouth or by rectum. Penicillin works about as well, but some worry it could provoke spasms, because it inhibits the GABA receptor that tetanospasmin has already disturbed.

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• 7. The Vaccine Effect

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  Tetanospasmin is so potent that it will likely kill before the immune system can respond. For that reason, unlike many infections, recovery from natural tetanus does not usually bring immunity.

  Vaccination with tetanus toxoid is the answer. The CDC recommends that adults receive a booster every ten years. Standard practice in many places is to give a booster to anyone with a puncture wound who cannot remember their last shot or who has had fewer than three doses in a lifetime. A significant wound in such a person also calls for tetanus immune globulin. A booster cannot always rescue the patient from the current wound, since antibodies can take up to two weeks to form.

  Children under the age of seven usually receive the combined DPT or DTaP vaccine, which also protects against diphtheria and pertussis. Older children and adults commonly receive Td, which covers tetanus and diphtheria, or Tdap, which adds acellular pertussis.

  In 1990, tetanus killed 356,000 people worldwide. By 2015 there were about 209,000 infections and about 59,000 deaths. In the United States, fewer than 40 cases a year have been reported since 2010, almost all in people who were never vaccinated.

  In 1998, neonatal tetanus was responsible for about 14% of all newborn deaths, roughly 215,000 babies, in many developing countries. By 2010 the worldwide toll was about 58,000. A public health campaign cut deaths from the newborn form by 90% between 1990 and 2010. By 2013, the disease had largely vanished from all but 25 countries.

  The World Health Organization certifies when a country has eliminated maternal or neonatal tetanus. That requires at least 2 years of rates at or below 1 case per 1,000 live births. In 1998, Uganda recorded 3,433 cases in newborn babies, and 2,403 of them died. After a major public health effort, Uganda was certified as having eliminated the disease in 2011.

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• 8. Hunting the Cause

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  Hippocrates gave an early description of the disease in the 5th century BC. Ancient civilizations already knew that wounds could lead to fatal muscle spasms, though the cause remained hidden for centuries.

  In 1884, Arthur Nicolaier isolated a strychnine-like toxin from free-living anaerobic soil bacteria. That same year, Antonio Carle and Giorgio Rattone, two pathologists at the University of Turin, showed for the first time that tetanus could be transmitted. They injected pus from a person who had died of the disease into the sciatic nerves of rabbits and watched the animals' reactions as the illness spread.

  Kitasato Shibasaburō isolated C. tetani from a human victim in 1891. He later showed that the organism caused disease when injected into animals and that specific antibodies could neutralize its toxin. In 1897, Edmond Nocard demonstrated that tetanus antitoxin gave humans passive immunity and could be used both to prevent and to treat the disease.

  In 1924, P. Descombey developed the toxoid vaccine. It was widely used in World War II to prevent tetanus from battle wounds. The word tetanus itself comes from the Greek τέτανος, which derives from τείνειν.

  Vitamin C was also tested against tetanus in historical trials, but those trials were of poor quality. There is therefore insufficient evidence that it can treat or prevent the disease.

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