TETANUS Tetanus (lockjaw) causes localized or generalized spasms of muscles resulting from tetanospasmin, a toxin produced by the bacterium

Clostridium tetani. P.260 Etiology C. tetani is commonly shed in the excreta of humans and other animals. Its spores are ubiquitous in the environment. They enter the body through puncture wounds, compound fractures, or wounds from blank cartridges and fireworks. Infection has been reported from contamination of operative wounds, burns, parenteral injections (particularly in heroin addicts), and through the umbilicus of the newborn. The mere deposition of spores of the organism is not sufficient for infection. Necrotic tissue and an associated pyogenic infection are necessary for germination of the bacteria and production of tetanospasmin. Prevention of tetanus is accomplished by immunization with toxoid (denatured toxin). Children should be immunized routinely and booster doses given every 10 years. Immediate booster immunization should be given to patients with penetrating wounds, unless a recent immunization may be documented. Immunity is not conferred by the disease, and patients should receive the toxoid and human tetanus immune globulin (HTIG), but at a different site. Pathogenesis Tetanospasmin is a single polypeptide chain of 1,315 amino acids, synthesized by a large bacterial plasmid. The toxin becomes active when nicked by a serine protease into small and large chains held together by a disulfide bridge. The large chain also contains an internal disulfide bridge, which appears to be necessary for penetration into the nerve cell. The small chain is responsible for toxin activity. Tetanospasmin prevents synaptic vesicles from fusing with the cell membrane and prevents the release of neurotransmitters. It appears to bind to synaptobrevin, a protein involved in the fusion process. Tetanospasmin is active at the neuromuscular junction, autonomic terminals, and most importantly in inhibitory neurons in the CNS, inhibiting the release of gamma-aminobutyric acid (GABA) and glycine. The central effects usually overwhelm the peripheral effects, although autonomic dysfunction may become evident, clinically. Access to the CNS is by retrograde transport in alpha-motor neurons. Hematogenous spread of the toxin before neuronal transport probably accounts for generalized tetanus. Pathology No pathologic changes occur in the central or peripheral nervous system except those caused secondarily by anoxia or other metabolic derangement. Incidence The disease is found throughout the world where it most commonly is found in puncture-wound infections of the extremities caused by nails or splinters. The incidence in developed countries has been dramatically reduced by immunization with denatured toxin (tetanus toxoid). In the United States about 50 cases per year are reported to the CDC. Worldwide, about 1 million cases occur; 50% are encountered in neonates because of nonsterile birthing technique. In the United States now, the infection is most common in narcotic addicts. The narcotic

is cut by admixing with quinine, a substance that favors the growth of the organisms at the site of the injection. Symptoms The incubation period is usually between 5 and 10 days. It may be as short as 3 days or as long as 3 weeks. The severity of the disease usually is greater when the incubation period is short. The symptoms may be localized or generalized. In the localized form, the spasms are confined to the injured limbs. This form is rare and is most commonly seen in patients who have been partially protected by prophylactic doses of antitetanic serum. When the portal of entrance is in the head (e.g., face, ear, tonsils), symptoms may be localized there (cephalic tetanus), with trismus, facial paralysis, and ophthalmoplegia. In the generalized form, a prominent symptom is stiffness of the jaw (trismus, lockjaw). This is followed by stiffness of the neck, irritability, and restlessness. As the disease progresses, stiffness of the muscles becomes generalized. Rigidity of the back muscles may become so extreme that the patient assumes the position of opisthotonos. Rigidity of the facial muscles gives a characteristic facial expression, the so-called risus sardonicus. Added to the stiffness of the muscles are paroxysmal tonic spasms that may occur spontaneously or may be precipitated by an external stimulus. Dysphagia may develop from spasm of the pharyngeal muscles; cyanosis and asphyxia may result from spasm of the glottis or respiratory muscles. Seizures may occur and are probably secondary to anoxia caused by the spasms. Temperature may be normal but more commonly is elevated to 101F to 103F. Laboratory Data No specific changes are found in blood, urine, or CSF. There is no specific laboratory test of confirmation. Diagnosis The diagnosis of tetanus is made by the characteristic signs (e.g., trismus, risus sardonicus, tonic spasms) in a patient with a wound of the skin and deeper tissues. Occasionally, however, a history of an antecedent wound is denied. The symptoms of strychnine poisoning differ from those of tetanus in that the muscles are relaxed between spasms and the jaw muscles are rarely involved. Other differential entities include black widow-spider bite, dystonic reactions, drug withdrawal, hypocalcemic tetany, stiff-man syndrome, status epilepticus, and rabies. Course and Prognosis The outlook is grave in all cases of generalized tetanus. The mortality rate is over 50%. Prognosis is best when the incubation period is long. The mortality rate is reduced by the prompt administration of serum and aggressive management of pulmonary and autonomic dysfunction. In fatal cases, death usually occurs in 3 to 10 days. Death is most commonly caused by respiratory compromise. In the patients who recover, there is a gradual reduction in the frequency and severity of spasms. Treatment

The patient should be treated in an intensive care unit. The wound should be surgically cleaned. Antiserum does not neutralize toxins that have been fixed in the nervous system, but it is administered to neutralize toxin that has not yet entered the nervous system. It is customary to administer HTIG in a dose of 3000 U to 6000 U, intramuscularly, as soon as the diagnosis is made, although as little as 500 U may be equally effective. Intrathecal HTIG therapy has been reported to decrease mortality. However, a meta-analysis concluded that intrathecal administration was not more effective than parenteral administration Penicillin G has been the antibiotic of choice for inhibiting further growth of the organisms. However, penicillin is a GABA antagonist. Metronidazole is therefore becoming the antibiotic of choice. Dirty wounds should be surgically debrided and cleaned. Tracheostomy should be performed to ensure adequate ventilation. Benzodiazepines are used commonly to control muscle spasms; high doses may be required. Benzodiazepines are also useful for immediate control of convulsions, but phenytoin or other suitable long-lasting anticonvulsant should be added if seizures occur. In severe cases, neuromuscular blockade may be necessary, in conjunction with the use of positive-pressure ventilation. Low dose anticoagulation with heparin then should be considered because the risk of pulmonary embolism is high in patients treated with blockade. For prevention, active immunization with tetanus toxoid should be given in infancy, with boosters at school entry about 7 years later, and then about every 10 years.