Tetanus (Clostridium tetani)

Etiology

Tetanus is an acute, spastic paralytic illness caused by a neurotoxin produced by Clostridium tetani. Thus, tetanus can be considered more as a toxin-mediated process than an acute infectious process, since there are few, if any, symptoms elicited by the presence of replicating microorganisms or host inflammatory response. Unlike other pathogenic clostridia species, C. tetani is not a tissue-invasive organism and instead causes illness through the 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.

Clostridium tetani is a motile, gram-positive, spore-forming obligate anaerobe. The organism's natural habitat worldwide is soil, dust, and the alimentary tracts of various animals. C. tetani forms spores terminally, with a classic morphologic appearance resembling a drumstick or tennis racket microscopically. The formation of spores is a critical aspect of the organism's persistence in the environment. Spores can survive boiling but not autoclaving, whereas the vegetative cells are killed by antibiotics, heat, and standard disinfectants.

Epidemiology

Tetanus occurs worldwide and is endemic in many developing countries, although its incidence varies considerably. Public health efforts in recent years have had an impressive impact on tetanus-associated mortality, although many challenges remain. Approximately 57,000 deaths were caused by tetanus globally in 2015. Of these, approximately 20,000 deaths occurred in neonates and 37,000 in older children and adults. Most mortality from neonatal (or umbilical) tetanus occurs in South Asia and Sub-Saharan Africa ( Fig. 238.1 ). Mortality in adults is largely caused by maternal tetanus, which results from postpartum, postabortal, or postsurgical wound infection with C. tetani. Reported tetanus cases in the United States have declined >95% since 1947, and deaths from tetanus have declined by >99% in that same period. From 2009 through 2015, a total of 197 cases and 16 deaths from tetanus were reported in the United States. The majority of U.S. childhood cases of tetanus 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 may also occur in the setting of illicit drug injection. The disease has been associated with 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. Rarely, cases may present to clinical attention without an antecedent history of trauma.

Pathogenesis

Tetanus typically occurs after spores (introduced by traumatic injury) germinate, multiply, and produce tetanus toxin. A plasmid carries the toxin gene. Toxin is produced only by the vegetative cell, not the spore. It is released after the vegetative phase of replication, with replication occurring under anaerobic conditions. The low oxidation-reduction potential of an infected injury site therefore provides an ideal environment for transition from the spore to the vegetative stage of growth. Following bacterial cell death and lysis, tetanospasmin is produced. The toxin has no known function for clostridia in the soil environment where they normally reside. Tetanus toxin is a 150 kDa simple protein consisting of a heavy (100 kDa) and a light (50 kDa) 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, facilitated by dyneins, 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; as a consequence, affected muscles sustain maximal contraction and cannot relax. This aspect of pathogenesis led to the term lockjaw , classically applied to the clinical manifestations of tetanus in the affected individual. The autonomic nervous system is also rendered unstable in tetanus.

The phenomenal potency of tetanus toxin is enzymatic. The 50 kDa light chain (A-chain) of tetanus toxin 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 cleavage of synaptobrevin is the final target of tetanus toxin, and even in low doses the neurotoxin will inhibit neurotransmitter exocytosis in the inhibitory interneurons. The blockage of GABA and glycine causes the physiologic effects of tetanus toxin. The 100 kDa heavy chain (B-chain) of the toxin contains its binding and internalization domains. It binds to disialogangliosides (GD2 and GD1b) on the neuronal membrane. The translocation domain aids the movement of the protein across that membrane and into the neuron.

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. In severe cases, only the back of the head and the heels of the patient are noted to be 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 duration of these seizures may range from a few seconds to a few minutes in length with intervening respite periods. 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 (104°F), is common and is caused by 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. It presents 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, which is typically the portal of entry for the microorganism, may retain 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.