Clostridium tetani (Tetanus)

Microbiology And Pathogenesis

C. tetani is a slender, gram-positive, nonencapsulated, motile, obligately anaerobic bacillus that exists in vegetative and sporulated forms. The genome of the organism has been sequenced. The sporulated form has a characteristic drumstick microscopic appearance because of the terminal position of spores. Spores are highly resistant to disinfection by chemicals or heat, but vegetative forms are susceptible to the bactericidal effect of heat (autoclaving at 121°C and 103 kPa [15 psi] for 15 minutes), to chemical disinfectants (iodine, glutaraldehyde, hydrogen peroxide), and to certain antibiotics.

Spores are ubiquitous in soil and the gut of mammals; they are dormant and nonpathogenic in soil or contaminated tissue until conditions are favorable for transformation to the vegetative, pathogenic form. Such conditions are those of locally decreased oxygen reduction potential as created in devitalized tissue by a foreign body, trauma (especially crush injury), or suppurative infection.

C. tetani is noninvasive and does not cause an inflammatory response or tissue destruction. Disease is initiated by exotoxins. Two toxins are produced, tetanolysin (of uncertain importance) and tetanospasmin (a potent neurotoxin responsible for clinical tetanus). Tetanospasmin, often referred to as “tetanus toxin,” is encoded on a plasmid present in all toxigenic strains, and it is released with growth of C. tetani at the site of infection. Tetanospasmin affects the neuromuscular end plates and the motor nuclei of the central nervous system, thereby causing skeletal muscle spasm and convulsions. Mechanisms of absorption and transport of tetanospasmin are not understood completely, but 2 mechanisms are speculated. If a large amount of tetanospasmin is produced, spread to neurons through the bloodstream and lymphatic system occurs, causing spasm at sites distant from the site of infection that first affect muscles with the shortest neural pathway. Lockjaw and risus sardonicus, often seen in generalized tetanus, reflect this pathophysiologic process and are associated with rapidly progressive, severe disease. From the site of production, small amounts of neurotoxin also can ascend the neural axis (and sometimes the spinal axis cranially) to cause localized tetanus. The timing of onset of muscle involvement is proportional to the neural distance from the site of injury.

The extracellular matrix proteins nidogen-1 and nidogen-2 serve as the tetanospasmin receptor. Tetanospasmin primarily gains access to the nervous system through the neuromuscular junction, where it migrates retrogradely transsynaptically, protected from neutralizing antitoxin, to affect inhibitory synapses, where it binds irreversibly to prevent release of acetylcholine. Uninhibited lower motor neurons increase tone of agonist and antagonist muscles, thereby causing characteristic localized spasms and rigidity.

Tetanospasmin also can prevent transmission at neuromuscular junctions and thus cause paralysis. The effect of the toxin on the brain is controversial; direct inoculation can cause seizures, but spasms of tetanus probably result from the spinal rather than the supraspinal action of tetanospasmin. Affected patients are fully conscious. Some clinical manifestations of tetanus suggest involvement of the sympathetic nervous system. The effect of tetanospasmin is permanent; recovery depends on ultrasprouting of neurons.

Clinical Manifestations

Tetanus is divided into clinical patterns that reflect host factors and the site of inoculation: generalized, localized, cephalic, and neonatal. In most cases, the site of injury, which often is minor, can be determined. Inability to identify a portal of entry does not exclude the diagnosis, especially in unimmunized people. The appearance of a wound is not helpful in diagnosis, but circumstances of occurrence are (e.g., severity of crush injury and soil contamination). In the US, most cases of tetanus occur after puncture wounds, farming or gardening activities, or the use of illicit drugs.

The interval between the time of injury and the appearance of symptoms has important prognostic significance; the shorter the interval (<7 days), the worse the prognosis. The frequency and severity of clinical manifestations depend on the amount of toxin that reaches the nervous system. The portal of entry also is an important prognostic factor. Certain injuries (e.g., compound fracture, puncture wound in a drug user) or infections (e.g., that following abortion, infection of a neonate’s umbilical stump, burn wound) have poor prognoses. Involvement of the autonomic nervous system portends a poor prognosis. Such data have been used to develop scoring systems to predict severity and prognosis.

Generalized Tetanus

Generalized tetanus, which is a neurologic disease manifesting as trismus, risus sardonicus (sardonic smile), stiff neck, dysphagia, periods of apnea, and severe muscular spasms, is the most common manifestation of tetanus, often occurring as a complication of localized tetanus that is recognized only in retrospect. The onset can be insidious over a period of 1–7 days. Trismus (lockjaw), the most common presenting symptom, commonly is mistaken as a manifestation of parapharyngeal infection or temporomandibular joint problems. A history of stiffness of the back or rigidity of the neck or abdomen frequently is recognized in retrospect. A subtle “sarcastic smile” (risus sardonicus) may be noticed, and rigidity of the abdominal muscles is detectable on examination.

As the disease progresses, additional muscle groups become involved, the most striking involvement being of the paraspinal musculature. The most dramatic feature of generalized tetanus is the very painful, generalized tetanic, opisthotonic spasm manifest as arching of the back (sometimes with just head and feet touching the bed) to resemble decorticate posturing ( Fig. 188.1 ). The force can produce fractures of the vertebrae or other bones and hemorrhage into muscles. The periodicity of tetanic spells can cause confusion with seizures; however, patients with tetanus, unlike patients with seizures, do not lose consciousness. Spasms often are triggered by sensory stimuli. Respiratory compromise during tetanic spells can be life-threatening; upper airway obstruction is common, and with additional involvement of abdominal and diaphragmatic muscle, apnea can occur.

Symptoms of autonomic overactivity generally are manifest in early phases as irritability, restlessness, sweating, and tachycardia. In later phases, hyperthermia, profuse sweating, cardiac arrhythmias, labile hypertension or hypotension, and fever commonly are present. Episodes of bradycardia and hypotension can lead to cardiac arrest. Cardiac arrest also has been attributed to myocardial damage caused by the high catecholamine level, as well as by toxic damage to the brainstem. Fever can result from sympathetic overactivity or from superinfections, such as pneumonia. Spasms and cardiovascular complications occur most commonly during the first week and resolve slowly during the ensuing 2–4 weeks.

Even with available treatment, generalized tetanus usually worsens in the first 2 weeks after diagnosis, with recovery occurring over the subsequent 3–5 weeks. If antitoxin is not given, disease persists for weeks to months until cessation of production and binding of tetanospasmin and the formation of new neuromuscular junctions.