TETANUS: A REVIEW

Raymond Towey,
Department of Anaesthesia, St.Mary's Hospital Lacor, Gulu, Uganda

PATHOPHYSIOLOGY		COMPLICATIONS
CLINICAL FEATURES		MORTALITY AND OUTCOME
SEVERITY GRADING		CONCLUSION
MANAGEMENT		References

Tetanus remains an important cause of death worldwide and is associated with a high mortality, particularly in the developing world. With modern intensive care management, death from acute respiratory failure should be prevented, but cardiovascular complications as a result of autonomic instability and other causes of death remain.1 In this article, the pathophysiology, clinical features, and current management of tetanus are reviewed.

In spite of the World Health Organization's intention to eradicate tetanus by the year 1995, it remains endemic in the developing world. The WHO estimated that there were approximately 1,000,000 deaths from tetanus worldwide in 1992. This included 580,000 deaths from neonatal tetanus, of which 210,000 were in South East Asia and 152,000 in Africa. The disease is uncommon in developed countries. In South Africa approximately 300 cases occur each year (6 per million head of population), approximately 12-15 cases are reported each year in Britain (0.2 per million) and between 50 and 70 in the USA (0.2 per million).

Tetanus is caused by a Gram-positive bacillus, Clostridium tetani. This is a common bacterium with a natural habitat in the soil. It can also be isolated from animals and human faeces. It is a motile, spore-forming obligate anaerobe. The spore is incompletely destroyed by boiling but eliminated by autoclaving at¹ atmosphere pressure and 120°C for 15 min. It is rarely cultured, as the diagnosis of the disease is clinical. Clostridium tetani produces its clinical effects via a powerful exotoxin. The role of the toxin within the organism is not known. The DNA for this toxin is contained in a plasmid. Presence of the bacterium does not always mean that the disease will occur, as not all strains possess the plasmid. Bacterial antimicrobial sensitivity has been little investigated.

As infection does not confer immunity, prevention is through vaccination. Tetanus vaccine has been available since 1923. Vaccination is started at 2 months of age with three injections performed at monthly intervals. The second injection confers immunity with the third prolonging its duration. A booster is given before the age of 5. Similar responses occur in older children and adults. Neonatal immunity is provided by maternal vaccination and transplacental transfer of immunoglobulin. This may be impaired in the presence of maternal HIV infection. Immunity is not life-long. Revaccination at 10-yr intervals is recommended in the USA. In the UK, two boosters spaced 10 years apart are recommended in adulthood, so the recommendations do not extend to vaccination beyond the third decade. Thus in the UK, after the 5 injections patients are considered immune, and there is no value in giving further prophylactic doses. In the USA, more than 70% of cases and 80% of deaths occur in those over 50. Similar proportions are reported in Europe.

PATHOPHYSIOLOGY

Under anaerobic conditions found in necrotic or infected tissue, the tetanus bacillus secretes two toxins: tetanospasmin and tetanolysin. Tetanolysin is capable of locally damaging viable tissue surrounding the infection and optimizing the conditions for bacterial multiplication.

Toxins

Tetanospasmin leads to the clinical syndrome of tetanus. It binds to neural membranes and the amino terminus facilitates cell entry. It acts pre-synaptically to prevent neurotransmitter release from affected neurones. Released tetanospasmin spreads to underlying tissue and binds to gangliosides on the membranes of local nerve terminals. If toxin load is high, some may enter the bloodstream from where it diffuses to bind to nerve terminals throughout the body. The toxin is then internalized and transported intra-axonally and retrogradely to the cell body. Transport occurs first in motor and later in sensory and autonomic nerves. Once in the cell body the toxin can diffuse out, affecting and entering nearby neurones. When spinal inhibitory interneurones are affected, symptoms occur. Further retrograde intraneural transport occurs with toxin spreading to the brainstem and midbrain. This passage includes retrograde transfer across synaptic clefts by a mechanism that is unclear.

Toxins and the CNS

The effects of the toxin result from prevention of neurotransmitter release. Synaptobrevin is a membrane protein necessary for the export of intracellular vesicles containing neurotransmitter. The tetanospasmin cleaves synaptobrevin, thereby preventing neurotransmitter release. The toxin has a predominant effect on inhibitory neurones, inhibiting release of glycine and gamma- aminobutyric acid (GABA). The term "disinhibition" is used as the main effect of tetanus. This results in a failure of inhibition (relaxation) of muscle groups leading to increased muscle tone and muscular spasms because the muscles are unable to relax. In normal muscles, when one muscle group contracts there has to be a corresponding relaxation of the opposing muscle group. In tetanus this is prevented and results in intermittent spasms. Interneurones inhibiting alpha motor neurones are first affected and the motor neurones lose inhibitory control. Later (because of the longer path), pre-ganglionic sympathetic neurones in the lateral horns and the parasympathetic centres are also affected. Motor neurones are similarly affected and the release of acetylcholine into the neuromuscular cleft is reduced. This effect is similar to the action of the closely related botulinum toxin, which produces a flaccid paralysis. However, in tetanus the disinhibitory effect on the motor neurone overwhelms any diminution of function at the neuromuscular junction. Medullary and hypothalamic centres may also be affected. Tetanospasmin has a cortical convulsant effect in animal studies. Whether these mechanisms contribute to intermittent spasm and autonomic storms is unclear. The pre-junctional effect on the neuromuscular junction may lead to considerable weakness between spasms, and might account for both the paralysis of cranial nerves observed in cephalic tetanus, and myopathies observed after recovery.

Uncontrolled disinhibited efferent discharge from motor neurones in the spinal cord and brainstem leads to intense muscular rigidity and spasm, which may mimic convulsions. The reflex inhibition of antagonist muscle groups is lost, and agonist and antagonist muscles contract simultaneously. Muscle spasms are intensely painful and may lead to fractures and tendon rupture. Muscles of the jaw, face, and head are often involved first because of their shorter axonal pathways. The trunk and limbs follow but peripheral muscles in the hands and feet are relatively spared (Figure 1)

Disinhibited autonomic discharge leads to disturbances in autonomic control, with sympathetic overactivity and excessive plasma catecholamine levels. Neuronal binding of toxin is thought to be irreversible. Recovery requires the growth of new nerve terminals, which explains the prolonged duration of tetanus.

CLINICAL FEATURES

Tetanus usually follows a recognized injury. Contamination of wounds with soil, manure, or rusty metal can lead to tetanus. It can complicate burns, ulcers, gangrene, necrotic snakebites, middle ear infections, septic abortions, childbirth, intramuscular injections, and surgery. Injuries may be trivial, and in up to 50% of cases the injury occurs indoors and/or is not considered serious enough to seek medical treatment. In 15-25% of patients, there is no evidence of a recent wound.

Presentation

There is a clinical triad of rigidity, muscle spasms and autonomic dysfunction. Neck stiffness, sore throat, and difficulty opening the mouth are often early symptoms. Masseter spasm causes trismus or 'lockjaw'. Spasm progressively extend to the facial muscles causing the typical facial expression, 'risus sardonicus', and muscles of swallowing causing dysphagia (figure 1). Rigidity of the neck muscles leads to retraction of the head. Truncal rigidity may lead to opisthotonos, which is the severe arching of the back during a spasm caused by the stronger extensor muscle group. Respiratory difficulty with decreased chest wall compliance may also ensue.

In addition to increased muscle tone, there are episodic muscular spasms. These tonic contractions have a convulsion-like appearance affecting agonist and antagonist muscle groups together. They may be spontaneous or triggered by touch, visual, auditory or emotional stimuli. Spasms vary in severity and frequency, but may be strong enough to cause fractures and tendon avulsions. Spasms may be almost continual, leading to respiratory failure. Pharyngeal spasms are often followed by laryngeal spasms and are associated with aspiration and life-threatening acute airway obstruction.

Generalized tetanus, the commonest form of tetanus affects all muscles throughout the body. The muscles of the head and neck are usually affected first with progressive caudal spread of rigidity and spasm to affect the whole body. The differential diagnosis includes orofacial infection, dystonic drug reactions, hypocalcaemia, strychnine poisoning, and hysteria.

Local tetanus is seen with lower toxin loads and peripheral injuries. Spasm and rigidity are restricted to a limited area of the body. Mortality is greatly reduced. An exception to this is cephalic tetanus when localized tetanus from a head wound affects the cranial nerves; paralysis rather than spasm predominates at presentation (figure 2) but progression to generalized tetanus is common and mortality is high.

Tetanus neonatorum causes more than 50% of deaths from tetanus worldwide but is very rare in developed countries. Neonates present within a week of birth with a short history of failure to feed, vomiting, and 'convulsions'. Seizures, meningitis, and sepsis are differential diagnoses. Spasms are generalized and mortality is high. Poor umbilical hygiene is the cause of the disease but it is entirely preventable by maternal vaccination, even during pregnancy.

Autonomic effects

Prior to the introduction of artificial ventilation, many patients with severe tetanus died from acute respiratory failure. With the development of intensive care and the ability to ventilate patients it became apparent that severe tetanus was associated with marked autonomic instability. The sympathetic nervous system is most prominently affected. Clinically, increased sympathetic tone causes persistent tachycardia and hypertension. Marked vasoconstriction and pyrexia are also seen. Basal plasma catecholamine levels are raised. 'Autonomic storms' occur with marked cardiovascular instability. Severe hypertension and tachycardia may alternate with profound hypotension, bradycardia, or recurrent cardiac arrest. These alterations are a result of rapid alterations in systemic vascular resistance, rather than problems with cardiac filling or performance. During these 'storms' plasma catecholamine levels are raised up to 10-fold, to levels similar to those seen in phaeochromocytoma. Norepinephrine (noradrenaline) is affected more than epinephrine (adrenaline). Neuronal hyperactivity rather than adrenal medullary hyperactivity appears to predominate.

In addition to the cardiovascular system, other autonomic effects include profuse salivation and increased bronchial secretions. Gastric stasis, ileus, diarrhoea, and high output renal failure may all be related to autonomic disturbance.

The involvement of the sympathetic nervous system is established. The role of the parasympathetic system is less clear. Tetanus has been reported to induce lesions in the vagal nuclei, while locally applied toxin may lead to excessive vagal activity. Hypotension, bradycardia, and asystole may arise from increased vagal tone and activity.

Natural history

The incubation period (time from injury to first symptom) averages 7-10 days, with a range of 1-60 days. The onset time (time from first symptom to first spasm) varies between 1-7 days. Shorter incubation and onset times are associated with more severe disease. The first week of the illness is characterized by muscle rigidity and spasms, which progressively increase in severity. Autonomic disturbance usually starts several days after the spasms, and persists for 1-2 weeks. Spasms reduce after 2-3 weeks, but stiffness may persist considerably longer. Recovery from the illness occurs because of re-growth of axon terminals and by toxin destruction.

SEVERITY GRADING

There are several grading systems but the system reported by Ablett is most widely used (table 1).

Altered cardiovascular physiology

In uncomplicated tetanus, the cardiovascular system mimics that of a normal patient undergoing intense exercise. There is a hyperdynamic circulation largely because of increased basal sympathetic activity and muscle metabolism, with a lesser effect from raised core temperature. There is low-normal systemic vascular resistance and raised cardiac output, because of extensive vasodilatation in metabolically active muscles. As the oxygen extraction ratio does not alter in tetanus, the increased demand must be delivered by increased blood flow. Poor spasm control exaggerates these effects. In severe tetanus, patients are less able to increase cardiac performance and are more susceptible to profound hypotension and shock during acute vasodilatory storms. The mechanism is unclear but may relate to sudden reduction of catecholamine secretion or a direct action of tetanus toxin on the myocardium. Altered myocardial function may occur due to persistently raised catecholamine levels, but abnormal function may occur even in the absence of sepsis or high catecholamine levels.

Altered respiratory physiology

Muscular rigidity and spasms of the chest wall, diaphragm, and abdomen lead to a restrictive defect. Pharyngeal and laryngeal spasms predict respiratory failure or life-threatening airway obstruction. Poor cough from rigidity, spasms, and sedation leads to atelectasis and the risk of pneumonia is high. The inability to swallow copious saliva, profuse bronchial secretions, pharyngeal spasms, raised intra-abdominal pressure, and gastric stasis all increase the risk of aspiration, which is common. Ventilation/ perfusion mismatch is also common. Consequently, hypoxia is a uniform finding in moderate or severe tetanus even when the chest is radiologically clear. When breathing air, oxygen tensions are often between 5.3-6.7kPa (40-50mmHg), with the oxygen saturation commonly falling below 80%. In artificially ventilated patients, increased A-a gradients persist. Oxygen delivery and utilization may be compromised even without super-added lung pathology. Acute respiratory distress syndrome may occur as a specific complication of tetanus. Minute ventilation may be altered by a variety of causes. Hyperventilation may occur because of fear, autonomic disturbance, or alteration in brainstem function. Hypocarbia (PaCO₂ 4.0-4.6 kPa (30-35mmHg) is usual in mild to moderate disease. Hyperventilation 'storms' may lead to severe hypocarbia (PaCO₂ <3.3 kPa (25mmHg). In severe disease, hypoventilation from prolonged spasms and apnoea occurs. Sedation, exhaustion and altered brainstem function may also lead to respiratory failure. Respiratory drive may be deficient leading to recurrent life-threatening apnoeic periods.

Altered renal physiology

In mild tetanus, renal function is preserved. In severe disease reduced, glomerular filtration rate and impaired renal tubular function are frequent. Contributory causes of renal failure include dehydration, sepsis, blocking of the renal tubule with myoglobin (as a result of muscle breakdown), and alterations in renal blood flow secondary to catecholamine surges. Renal failure may be oliguric or polyuric. Clinically important renal impairment is associated with autonomic instability and histology is normal or shows acute tubular necrosis.

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