Etiology

Tetanus is an acute, spastic paralytic illness historically called lockjaw that is caused by the neurotoxin produced by Clostridium tetani, a motile, gram-positive, spore-forming obligate anaerobe whose natural habitat worldwide is soil, dust, and the alimentary tracts of various animals. C. tetani forms spores terminally, producing a drumstick or tennis racket appearance microscopically. Tetanus spores can survive boiling but not autoclaving, whereas the vegetative cells are killed by antibiotics, heat, and standard disinfectants. Unlike many clostridia, C. tetani is not a tissue-invasive organism and instead causes illness through the effects of a single toxin, tetanospasmin, more commonly referred to as tetanus toxin. Tetanospasmin is the 2nd most poisonous substance known, surpassed in potency only by botulinum toxin. The human lethal dose of tetanus toxin is estimated to be 10⁻⁵ mg/kg.

Epidemiology

Tetanus occurs worldwide and is endemic in approximately 90 developing countries, although its incidence varies considerably. The most common form, neonatal (or umbilical) tetanus, kills approximately 500,000 infants each year, with about 80% of deaths in just 12 tropical Asian and African countries. It occurs in infants whose mothers are not immunized. In addition, an estimated 15,000-30,000 unimmunized women worldwide die each year of maternal tetanus, which results from postpartum, postabortal, or postsurgical wound infection with C. tetani. Approximately 50 cases of tetanus are reported each year in the USA, mostly in persons >60 yr of age, although cases also occur in toddlers and neonates. Approximately 20% of children in the USA 10-16 yr of age lack a protective antibody level. The majority of childhood cases of tetanus in the USA have occurred in unimmunized children whose parents objected to vaccination.

Most non-neonatal cases of tetanus are associated with a traumatic injury, often a penetrating wound inflicted by a dirty object such as a nail, splinter, fragment of glass, or unsterile injection. Tetanus occurring after illicit drug injection is becoming more common. The disease also occurs after the use of contaminated suture material and after intramuscular injection of medicines, most notably quinine for chloroquine-resistant falciparum malaria. The disease may also occur in association with animal bites, abscesses (including dental abscesses), ear and other body piercing, chronic skin ulceration, burns, compound fractures, frostbite, gangrene, intestinal surgery, ritual scarification, infected insect bites, and female circumcision. Rare cases have no history of trauma.

Pathogenesis

Tetanus occurs after introduced spores germinate, multiply, and produce tetanus toxin in the low oxidation-reduction potential (E_h) of an infected injury site. A plasmid carries the toxin gene. Toxin is released after vegetative bacterial cell death and lysis. Tetanus toxin (and the botulinum toxins) is a 150-kd simple protein consisting of a heavy chain (100 kd) and a light (50 kd) chain joined by a single disulfide bond. Tetanus toxin binds at the neuromuscular junction and enters the motor nerve by endocytosis, after which it undergoes retrograde axonal transport to the cytoplasm of the α-motoneuron. In the sciatic nerve, the transport rate was found to be 3.4 mm/hr. The toxin exits the motoneuron in the spinal cord and next enters adjacent spinal inhibitory interneurons, where it prevents release of the neurotransmitters glycine and γ-aminobutyric acid (GABA). Tetanus toxin thus blocks the normal inhibition of antagonistic muscles on which voluntary coordinated movement depends; in consequence, affected muscles sustain maximal contraction and cannot relax. The autonomic nervous system is also rendered unstable in tetanus.

The phenomenal potency of tetanus toxin is enzymatic in nature. The light chain of tetanus toxin (and of several botulinum toxins) is a zinc-containing endoprotease whose substrate is synaptobrevin, a constituent protein of the docking complex that enables the synaptic vesicle to fuse with the terminal neuronal cell membrane. The heavy chain of the toxin contains its binding and internalization domains.

Because C. tetani is not an invasive organism, its toxin-producing vegetative cells remain where introduced into the wound, which may display local inflammatory changes and a mixed bacterial flora.

Clinical Manifestations

Tetanus is most often generalized but may also be localized. The incubation period typically is 2-14 days but may be as long as months after the injury. In generalized tetanus, the presenting symptom in about half of cases is trismus (masseter muscle spasm, or lockjaw). Headache, restlessness, and irritability are early symptoms, often followed by stiffness, difficulty chewing, dysphagia, and neck muscle spasm. The so-called sardonic smile of tetanus (risus sardonicus) results from intractable spasms of facial and buccal muscles. When the paralysis extends to abdominal, lumbar, hip, and thigh muscles, the patient may assume an arched posture of extreme hyperextension of the body, or opisthotonos, with the head and the heels bent backward and the body bowed forward with only the back of the head and the heels touching the supporting surface. Opisthotonos is an equilibrium position that results from unrelenting total contraction of opposing muscles, all of which display the typical boardlike rigidity of tetanus. Laryngeal and respiratory muscle spasm can lead to airway obstruction and asphyxiation. Because tetanus toxin does not affect sensory nerves or cortical function, the patient unfortunately remains conscious, in extreme pain, and in fearful anticipation of the next tetanic seizure. The seizures are characterized by sudden, severe tonic contractions of the muscles, with fist clenching, flexion, and adduction of the arms and hyperextension of the legs. Without treatment, the seizures range from a few seconds to a few minutes in length with intervening respite periods, but as the illness progresses, the spasms become sustained and exhausting. The smallest disturbance by sight, sound, or touch may trigger a tetanic spasm. Dysuria and urinary retention result from bladder sphincter spasm; forced defecation may occur. Fever, occasionally as high as 40°C, is common because of the substantial metabolic energy consumed by spastic muscles. Notable autonomic effects include tachycardia, dysrhythmias, labile hypertension, diaphoresis, and cutaneous vasoconstriction. The tetanic paralysis usually becomes more severe in the 1st wk after onset, stabilizes in the 2nd wk, and ameliorates gradually over the ensuing 1-4 wk.

Neonatal tetanus, the infantile form of generalized tetanus, typically manifests within 3-12 days of birth as progressive difficulty in feeding (sucking and swallowing), associated hunger, and crying. Paralysis or diminished movement, stiffness and rigidity to the touch, and spasms, with or without opisthotonos, are characteristic. The umbilical stump may hold remnants of dirt, dung, clotted blood, or serum, or it may appear relatively benign.

Localized tetanus results in painful spasms of the muscles adjacent to the wound site and may precede generalized tetanus. Cephalic tetanus is a rare form of localized tetanus involving the bulbar musculature that occurs with wounds or foreign bodies in the head, nostrils, or face. It also occurs in association with chronic otitis media. Cephalic tetanus is characterized by retracted eyelids, deviated gaze, trismus, risus sardonicus, and spastic paralysis of the tongue and pharyngeal musculature.

Diagnosis

The picture of tetanus is one of the most dramatic in medicine, and the diagnosis may be established clinically. The typical setting is an unimmunized patient (and/or mother) who was injured or born within the preceding 2 wk, who presents with trismus, other rigid muscles, and a clear sensorium.

Results of routine laboratory studies are usually normal. A peripheral leukocytosis may result from a secondary bacterial infection of the wound or may be stress induced from the sustained tetanic spasms. The cerebrospinal fluid is normal, although the intense muscle contractions may raise intracranial pressure. Neither the electroencephalogram nor the electromyogram shows a characteristic pattern. C. tetani is not always visible on Gram stain of wound material and is isolated in only about 30% of cases.

Differential Diagnosis

Fully developed, generalized tetanus cannot be mistaken for any other disease. However, trismus may result from parapharyngeal, retropharyngeal, or dental abscesses or, rarely, from acute encephalitis involving the brainstem. Either rabies or tetanus may follow an animal bite, and rabies may manifest as trismus with seizures. Rabies may be distinguished from tetanus by hydrophobia, marked dysphagia, predominantly clonic seizures, and pleocytosis (Chapter 266). Although strychnine poisoning may result in tonic muscle spasms and generalized seizure activity, it seldom produces trismus, and unlike in tetanus, general relaxation usually occurs between spasms. Hypocalcemia may produce tetany that is characterized by laryngeal and carpopedal spasms, but trismus is absent. Occasionally, epileptic seizures, narcotic withdrawal, or other drug reactions may suggest tetanus.

Treatment

Management of tetanus requires eradication of C. tetani and the wound environment conducive to its anaerobic multiplication, neutralization of all accessible tetanus toxin, control of seizures and respiration, palliation, provision of meticulous supportive care, and, finally, prevention of recurrences.

Surgical wound excision and debridement are often needed to remove the foreign body or devitalized tissue that created anaerobic growth conditions. Surgery should be performed promptly after administration of human tetanus immunoglobulin (TIG) and antibiotics. Excision of the umbilical stump in the neonate with tetanus is no longer recommended.

Tetanus toxin cannot be neutralized by TIG after it has begun its axonal ascent to the spinal cord. TIG should be given as soon as possible in order to neutralize toxin that diffuses from the wound into the circulation before the toxin can bind at distant muscle groups. The optimal dose of TIG has not been determined. A single intramuscular injection of 500 U of TIG is sufficient to neutralize systemic tetanus toxin, but total doses as high as 3,000-6,000 U are also recommended. Infiltration of TIG into the wound is now considered unnecessary. If TIG is unavailable, use of human intravenous immunoglobulin (IVIG) may be necessary. IVIG contains 4-90 U/mL of TIG; the optimal dosage of IVIG for treating tetanus is not known, and its use is not approved for this indication. Another alternative is equine- or bovine-derived tetanus antitoxin (TAT). The usual dose of TAT is 50,000-100,000 U, with half given intramuscularly and half intravenously, but as little as 10,000 U may be sufficient. TAT is not available in the USA. Approximately 15% of patients given the usual dose of TAT experience serum sickness. When TAT is used, it is essential to check for possible sensitivity to horse serum; desensitization may be needed. The human-derived immunoglobulins are much preferred because of their longer half-lives (30 days) and the virtual absence of allergic and serum sickness adverse effects. Intrathecal TIG, given to neutralize tetanus toxin in the spinal cord, is not effective.

Penicillin G (100,000 U/kg/day divided every 4-6 hr IV for 10-14 days) remains the antibiotic of choice because of its effective clostridiocidal action and its diffusibility, which is an important consideration because blood flow to injured tissue may be compromised. Metronidazole (500 mg every 8hr IV for adults) appears to be equally effective. Erythromycin and tetracycline (for persons >8 yr of age) are alternatives for penicillin-allergic patients.

All patients with generalized tetanus need muscle relaxants. Diazepam provides both relaxation and seizure control. The initial dose of 0.1-0.2 mg/kg every 3-6 hr given intravenously is subsequently titrated to control the tetanic spasms, after which the effective dose is sustained for 2-6 wk before a tapered withdrawal. Magnesium sulfate, other benzodiazepines (midazolam), chlorpromazine, dantrolene, and baclofen are also used. Intrathecal baclofen produces such complete muscle relaxation that apnea often ensues; like most other agents listed, baclofen should be used only in an intensive care unit setting. The highest survival rates in generalized tetanus are achieved with neuromuscular blocking agents such as vecuronium and pancuronium, which produce a general flaccid paralysis that is then managed by mechanical ventilation. Autonomic instability is regulated with standard α- or β- (or both) blocking agents; morphine has also proved useful.

Supportive Care

Meticulous supportive care in a quiet, dark, secluded setting is most desirable. Because tetanic spasms may be triggered by minor stimuli, the patient should be sedated and protected from all unnecessary sounds, sights, and touch, and all therapeutic and other manipulations must be carefully scheduled and coordinated. Endotracheal intubation may not be required, but it should be done to prevent aspiration of secretions before laryngospasm develops. A tracheostomy kit should be immediately at hand for unintubated patients. Endotracheal intubation and suctioning easily provoke reflex tetanic seizures and spasms, so early tracheostomy should be considered in severe cases not managed by pharmacologically induced flaccid paralysis. Therapeutic botulinum toxin has been used for this purpose, that is, to overcome trismus.

Cardiorespiratory monitoring, frequent suctioning, and maintenance of the patient’s substantial fluid, electrolyte, and caloric needs are fundamental. Careful nursing attention to mouth, skin, bladder, and bowel function is needed to avoid ulceration, infection, and obstipation. Prophylactic subcutaneous heparin may be of value but must be balanced with the risk for hemorrhage.

Complications

The seizures and the severe, sustained rigid paralysis of tetanus predispose the patient to many complications. Aspiration of secretions and pneumonia may have begun before the first medical attention was received. Maintaining airway patency often mandates endotracheal intubation and mechanical ventilation with their attendant hazards, including pneumothorax and mediastinal emphysema. The seizures may result in lacerations of the mouth or tongue, in intramuscular hematomas or rhabdomyolysis with myoglobinuria and renal failure, or in long bone or spinal fractures. Venous thrombosis, pulmonary embolism, gastric ulceration with or without hemorrhage, paralytic ileus, and decubitus ulceration are constant hazards. Excessive use of muscle relaxants, which are an integral part of care, may produce iatrogenic apnea. Cardiac arrhythmias, including asystole, unstable blood pressure, and labile temperature regulation reflect disordered autonomic nervous system control that may be aggravated by inattention to maintenance of intravascular volume needs.

Prognosis

Recovery in tetanus occurs through regeneration of synapses within the spinal cord and thereby the restoration of muscle relaxation. However, because an episode of tetanus does not result in the production of toxin-neutralizing antibodies, active immunization with tetanus toxoid at discharge with provision for completion of the primary series is mandatory.

The most important factor that influences outcome is the quality of supportive care. Mortality is highest in the very young and the very old. A favorable prognosis is associated with a long incubation period, absence of fever, and localized disease. An unfavorable prognosis is associated with onset of trismus <7 days after injury and with onset of generalized tetanic spasms <3 days after onset of trismus. Sequelae of hypoxic brain injury, especially in infants, include cerebral palsy, diminished mental abilities, and behavioral difficulties. Most fatalities occur within the 1st wk of illness. Reported case fatality rates for generalized tetanus are 5-35%, and for neonatal tetanus they extend from <10% with intensive care treatment to >75% without it. Cephalic tetanus has an especially poor prognosis because of breathing and feeding difficulties.

Prevention

Tetanus is an entirely preventable disease. A serum antibody titer of ≥0.01 U/mL is considered protective. Active immunization should begin in early infancy with combined diphtheria toxoid–tetanus toxoid–acellular pertussis (DTaP) vaccine at 2, 4, and 6 mo of age, with a booster at 4-6 yr of age and at 10-yr intervals thereafter throughout adult life (tetanus and reduced diphtheria toxoid [Td] or tetanus, and reduced diphtheria and pertussis toxoids [Tdap]). Immunization of women with tetanus toxoid prevents neonatal tetanus, and the World Health Organization is currently engaged in a global campaign for elimination of neonatal tetanus through maternal immunization with at least 2 doses of tetanus toxoid. For unimmunized persons >7 yr of age, the primary immunization series consists of 3 doses of Td toxoid given intramuscularly, with the 2nd given 4-6 wk after the 1st and the 3rd given 6-12 mo after the 2nd.

Arthus reactions (type III hypersensitivity reactions), a localized vasculitis associated with deposition of immune complexes and activation of complement, are reported rarely after tetanus vaccination. Mass immunization campaigns in developing countries have occasionally provoked a widespread hysterical reaction.