# 26 TETANUS

(Definition) Tetanus is an acute disease manifested by hypertonia, painful muscular contractions, and generalized
muscle spasms accompanied by autonomic nervous system disturbance without other apparent medical cause. With
the advent of widespread vaccination, the incidence of tetanus has drastically decreased especially in developed
countries. (Etiopathogenesis) Tetanus is caused by a powerful neurotoxin produced by the bacterium Clostridium
tetani. C. tetani is an anaerobic, gram-positive, spore-forming rod whose spores are highly resilient and can survive
readily in the environment throughout the world. Spores resist boiling and many disinfectants. The spores or
bacteria enter the body through abrasions or wounds. Once in a suitable anaerobic environment, the organisms
grow, multiply, and release tetanus toxin, an exotoxin that enters the nervous system and causes disease. Very low
concentrations of this highly potent toxin can result in tetanus (minimal lethal human dose, 2.5 ng/kg). Superficial
abrasions to the limbs are the most common infection sites in adults. Deeper infections (e.g., attributable to open
fracture or drug injection) are associated with more severe disease and worse outcomes. Only those bacteria
producing tetanus toxin (tetanospasmin) can cause tetanus. Tetanus toxin undergoes retrograde transport into the
central nervous system (CNS) and thus produces clinical effects different from those caused by the botulinum toxins,
which remain at the neuromuscular junction. Tetanus toxin is intraaxonally transported to motor nuclei of the
cranial nerves or ventral horns of the spinal cord. This toxin is produced as a single 150-kDa protein that is cleaved
to produce heavy (100-kDa) and light (50-kDa) chains linked by a disulfide bond and noncovalent forces. The carboxy
terminal of the heavy chain binds to specific membrane components in presynaptic α-motor nerve terminals;
evidence suggests binding to both polysialogangliosides and membrane proteins. This binding results in toxin
internalization and uptake into the nerves. Once inside the neuron, the toxin enters a retrograde transport pathway,
whereby it is carried proximally to the motor neuron body in what appears to be a highly specific process. Tetanus
toxin is transported in a carefully regulated pH-neutral environment that prevents an acid-induced conformational
change that would result in light-chain expulsion into the surrounding cytosol. The next stage in toxin trafficking is
less clearly understood but involves tetanus toxin’s escaping normal lysosomal degradation processes and
undergoing translocation across the synapse to the GABAergic presynaptic inhibitory interneuron terminals. Here
the light chain cleaves vesicle associated membrane protein 2 (VAMP2, also known as synaptobrevin). This molecule
is necessary for presynaptic binding and release of neurotransmitter; thus tetanus toxin prevents transmitter
release and effectively blocks inhibitory interneuron discharge. The result is unregulated activity in the motor
nervous system. Similar activity in the autonomic system accounts for the characteristic features of skeletal muscle
spasm and autonomic system disturbance. (Clinical Manifestations) Tetanus produces a wide spectrum of clinical
features that are broadly divided into generalized and local. In the usually mild form of local tetanus, only isolated
areas of the body are affected and only small areas of local muscle spasm may be apparent. If the cranial nerves are
involved in localized cephalic tetanus, the pharyngeal or laryngeal muscles may spasm, with consequent aspiration
or airway obstruction, and the prognosis may be poor. In the typical progression of generalized tetanus, muscles of
the face and jaw often are affected first, presumably because of the shorter distances toxin must travel up motor
nerves to reach presynaptic terminals. In assessing prognosis, the speed at which tetanus develops is important. The
incubation period (time from wound to first symptom) and the period of onset (time from first symptom to first
generalized spasm) are of particular significance; shorter times are associated with worse outcome. The most
common initial symptoms are trismus (lockjaw), muscle pain and stiffness, back pain, and difficulty swallowing. As
the disease progresses, muscle spasm develops. Generalized muscle spasm can be very painful. Commonly, the
laryngeal muscles are involved early or even in isolation. This is a life-threatening event as complete airway
obstruction may ensue. Spasm of the respiratory muscles results in respiratory failure. Without ventilatory support,
respiratory failure is the most common cause of death in tetanus. Autonomic disturbance is maximal during the
second week of severe tetanus, and death due to cardiovascular events becomes the major risk. Blood pressure is
usually labile, with rapid fluctuations from high to low accompanied by tachycardia. Episodes of bradycardia and
heart block also can occur. Autonomic involvement is evidenced by gastrointestinal stasis, sweating, increased
tracheal secretions, and acute (often high-output) renal failure. (Diagnosis) The diagnosis of tetanus is based on
clinical findings. There are no laboratory tests to diagnose tetanus. Culture of C. tetani from a wound provides
supportive evidence because not all strains exhibit the toxins. Serum anti-tetanus immunoglobulin G also may rule
out suspected tetanus because serum levels >0.1 IU/mL (measured by standard ELISA) are deemed protective and
do not support the diagnosis of tetanus. The most important thing to remember is that treatment should not be
delayed while these laboratory tests are being conducted. (Management) If possible, the entry wound should be
identified, cleaned, and debrided of necrotic material in order to remove anaerobic foci of infection and prevent
further toxin production. Metronidazole (400 mg rectally or 500 mg IV every 6 h for 7 days) is preferred for
antibiotic therapy. An alternative is penicillin (100,000–200,000 IU/kg per day), although this drug theoretically may
exacerbate spasms and in one study was associated with increased mortality. Antitoxin should be given early in an
attempt to deactivate any circulating tetanus toxin and prevent its uptake into the nervous system. Two
preparations are available: human tetanus immune globulin (TIG) and equine antitoxin. TIG is the preparation of
choice, as it is less likely to be associated with anaphylactoid reactions. A single IM dose (3000–5000 IU) is given,
with a portion injected around the wound. Equine-derived antitoxin is available widely and is used in low-income
countries; after hypersensitivity testing, 10,000–20,000 U is administered IM as a single dose or as divided doses.
Spasms are controlled by heavy sedation with benzodiazepines. Chlorpromazine and phenobarbital are commonly
used worldwide, and IV magnesium sulfate has been used as a muscle relaxant. A significant problem with all these
treatments is that the doses necessary to control spasms also cause respiratory depression; thus, in resource-limited
settings without mechanical ventilators, controlling spasms while maintaining adequate ventilation is problematic,
and respiratory failure is a common cause of death. In locations with ventilation equipment, severe spasms are best
controlled with a combination of sedatives or magnesium and relatively short-acting, cardiovascularly inert,
nondepolarizing neuromuscular blocking agents that allow titration against spasm intensity. It is important to
establish a secure airway early in severe tetanus. Ideally, patients should be nursed in calm, quiet environments
because light and noise can trigger spasms. Tracheal secretions are increased in tetanus, and dysphagia due to
pharyngeal involvement combined with hyperactivity of laryngeal muscles makes endotracheal intubation difficult.
Patients may need ventilator support for several weeks. Thus tracheostomy is the usual method of securing the
airway in severe tetanus. Cardiovascular instability in severe tetanus is notoriously difficult to treat. Rapid
fluctuations in blood pressure and heart rate can occur. Cardiovascular stability is improved by increasing sedation
with IV magnesium sulfate (plasma concentration, 2–4 mmol/L or titrated against disappearance of the patella
reflex), morphine, fentanyl, or other sedatives. In addition, drugs acting specifically on the cardiovascular system
(e.g., esmolol, calcium antagonists, and inotropes) may be required. Short-acting drugs that allow rapid titration are
preferred; Recovery from tetanus may take 4–6 weeks. Patients must be given a full primary course of
immunization, as tetanus toxin is poorly immunogenic and the immune response following natural infection is
inadequate. For the prognosis, the rapid development of tetanus is associated with more severe disease and poorer
outcome; it is important to note time of onset and length of incubation period. Tetanus is prevented by good wound
care and immunization The WHO guidelines for tetanus vaccination consist of a primary course of three doses in
infancy, boosters at 4–7 and 12–15 years of age, and one booster in adulthood. Individuals sustaining tetanus-prone
wounds should be immunized if their vaccination status is incomplete or unknown or if their last booster was given
>10 years earlier. Patients with an inadequate vaccine status who sustain wounds not classified as clean or minor
should also undergo passive immunization with TIG. It is recommended that tetanus toxoid be given in conjunction
with diphtheria toxoid in a preparation with or without acellular pertussis: DTaP for children <7 years old, Td for 7-
to 9-year-olds, and Tdap for children >9 years old and adults.