Unforgettable tetanus

Abstract

Introduction Tetanus has been known since Hippocrates. There have been few, if any, additions to its symptomatology though the pathophysiology has been explored to a molecular level and options for prevention and management have changed enormously. Active immunization programmes have been pursued for over 50 years and new technologically based management strategies have been developed over the past 30 years. In principle, tetanus should by now be a totally preventable disease but, even so, it is expected to have killed 10 million people in the last decade of the 20th century, the majority of them infants [1]. It continues to drain the meagre health resources of many developing countries, and to provide more occasional but nonetheless unpleasant surprises in more developed ones, appearing, as it does in several forms and guises, besides the classic picture following recognized trauma or wounding [2,3]. Reporting, incidences and mortality Tetanus is a notifiable disease in many countries, China being an exception eminently notable in view of its size and population. Overall figures may be reported, or reporting may be in terms of a number of recognized subtypes such as neonatal and maternal tetanus. Even where notification is compulsory, gross under-reporting is commonplace. Routine reporting systems for neonatal tetanus identified only about 4% of the cases estimated to have occurred worldwide in 1990 [4]. In the USA, the completeness of overall reporting to the national surveillance system between 1979 and 1984 was estimated to be 22–46% [5] and, in Switzerland, the reported cases of tetanus probably reflected no more than 13% of the actual number [6]. The available figures reflect a complex of geographical differences in reporting, lifestyle-related predisposition, application of preventative measures such as active immunization programmes, and therapeutic interventions such as the administration of antitoxin and technologically demanding treatments for the manifestations of the disease. The WHO estimates that, in 1992, there were 578 000 infant deaths from neonatal tetanus. Of these, 210 000 occurred in South East Asia, 152 000 in Africa, 114 000 in the Western Pacific region, 90 000 in the Eastern Mediterranian, 112 00 in the Americas and 1000 in Europe [6]. Table 1 summarizes recently published information on aspects of tetanus from different parts of the world. There have been many contributions to the literature from Russia but little is known of the incidence in Russia or in Eastern Europe. The incidence of maternal tetanus is not known. Probably 15 000 to 30 000 cases of maternal tetanus occur worldwide each year [17]: 27% can be attributed to post-abortal and 67% to post-partum sepsis. In Nigeria, 10% of adult tetanus cases were attributed to maternal tetanus [18].Table 1: Global prevalence of tetanus Pathophysiology Tetanus is a toxic infection caused by the obligate anaerobe Clostridium tetani. Clostridial toxins are generally regarded as the most poisonous substances known to mankind. The spores of Clostridium tetani are present in the soil and faeces and can enter the body, proliferate in devitalized tissue and produce the exotoxins, tetanospasmin and tetanolysin, which can gain access to the blood and central nervous system (CNS). Tetanolysin is a haemolysin but plays no presently recognized part in the overall clinical picture in tetanus. Tetanospasmin is primarily a very potent neurotoxin and is probably solely responsible for the manifestations of the disease. Access of the toxin to the CNS The toxin can circulate in the blood stream but does not enter the central nervous system in appreciable amounts by this route because it cannot cross the blood brain barrier except where it is deficient at the fourth ventricle. It enters motor nerves at the neuromuscular junction and travels by intra-axonal transmission at the rate of 72–250 mm day−1. It may thus take 2–14 days to reach the central nervous system. The symptoms appear only after the toxin has gained access to the presynaptic terminals of those inhibitory Renshaw cells that release gamma-aminobutyric acid (GABA) and glycine (rather than those that release acetylcholine). This blocks inhibition at brain stem and spinal cord level resulting initially in more or less localized increases in resting muscle tone (rigidity) and later in more generalized hyperreflexia and spasms [19]. The toxin enters sensory and autonomic nerves via their peripheral endings but, because of slower intra-axonal transport, it takes longer for the toxin to reach the lateral horn cells and autonomic dysfunction sets in a few days after the spasms. Autonomic dysfunction manifests as increased basal sympathetic activity and episodes of sympathetic overactivity or 'crises' involving both alpha and beta receptors. These are caused by reduced inhibition of the postsynaptic sympathetic fibres and adrenal medulla and are evidenced by outpourings of noradrenaline and adrenaline in amounts comparable with those found in patients with phaeochromocytoma (which are about ten times the basal amounts) [20,21]. Another postulated cause is the increased release of thyroid hormone and direct inhibition of the release of endogenous opioid oligopeptides. The cellular actions of tetanus toxin The principal site of action of tetanospasmin in mammals is at inhibitory synapses, though it can also affect the central excitatory synapses, the neuromuscular junction, and autonomic ganglia [22,23]. Injection of tetanus toxin into the hippocampus of the rat establishes a long lasting excitatory focus in the brain [24]. The convulsant effect either releases an inherent tendency for hippocampal nerve cells to fire repetitively or may preferentially block key inhibitory synapses, leaving excitatory influences unchecked. Whatever the cause, an excitatory effect at one group of neurones will have a secondary kindling effect on the other synapses within the brain which will reinforce and maintain the excitatory effect, and promote its extension from any primary focus. Tetanospasmin was initially thought to affect only glycinergic pathways, but effects were subsequently found on pathways mediated by GABA, which is probably the most widespread inhibitory transmitter in the mammalian nervous system. It now appears that the toxin can also interfere with other central inhibitory neurotransmitter processes such as those mediated by dopamine and noradrenaline, as well as transmission at cholinergic synapses in the peripheral somatic and autonomic nervous system [25,26]. Egea et al.[27] found that tetanus toxin blocks the release of acetyl choline from isolated nerve terminals in a dose-dependent manner, an effect prevented by antiserum to tetanus toxin. In GABA-ergic synapses that have been blocked by toxin, the responses to exogenously applied transmitter are unaffected. It follows that the effect is presynaptic, involving some aspect of events leading to release of endogenous transmitter. Tetanus toxin blocks the rearrangement of intramembrane particles at the plasma membrane of experimentally poisoned synapses. It has no effect on uptake, synthesis or storage of transmitter, but directly impairs the calcium-dependent release of GABA [28,29]. It blocks, not only the evoked release of transmitter, but also most of the spontaneous release. The blockade may be preceded by an asynchronous release of quanta of GABA. These effects are believed to result from interference with the movement of synaptic vesicles to the active zones through blockade of most of the calcium channels, because the toxin can selectively block the calcium component of the action potential in cultured neuroblastoma cells. The effects of tetanus toxin are prevented by pretreatment with ethanolamine O-sulphate or sodium valproate, drugs that enhance GABA-ergic mechanisms by inhibiting the enzyme GABA transaminase and/or succinic aldehyde dehydrogenase [30]. At a molecular level, tetanospasmin is synthesized as a single polypeptide chain with a molecular weight of 140 000–160 000, which can be enzymatically split into light and heavy chains. The carboxy terminus of the heavy chain mediates binding to the target cell membrane and the amino terminus mediates the incorporation of the toxin into the cell. Transmitter release at nerve terminals appears to be inhibited by the light chain which may interfere with exocytosis after the entry of calcium ions [2]. The light chain is a zinc endopeptidase that produces a single-site cleavage of an integral membrane protein of small synaptic vesicles, synaptobrevin. Clinical features The precipitating injury A history of some sort of injury is present in most cases, with an incubation period that can vary but is usually between 3 days and 3 weeks. However, the culprit wound may well be so trivial that the victim does not think of seeking medical attention. Tetanus may also occur following skin and middle ear infections [31]. Dental caries or a root canal procedure was considered to be the point of entry for tetanus spores in one instance [32]. Other unusual sources of injury include frostbite, gum ulceration by dentures, infected molluscum contagiosum, scratched atheroma cutis and infected granuloma pyogenicum. Thus it is unwise to exclude tetanus from a differential diagnosis just because there is no obvious portal of entry [33,34]. A series of cases of tetanus with a 96% mortality has been reported after intramuscular injections of quinine which are widely used in treatment. Quinine dihydrochloride, the usual formulation for parenteral administration has a pH of 2 and may cause local vasoconstriction and necrosis. The chemical damage and ischaemia lowers the redox potential at the injection site and provides a favourable milieu for rapid sporulation and growth of Clostridium tetani [35]. In another series reported in 1994, 89% of the cases were heroin addicts [36]. It may be relevant that heroin is often 'cut' with quinine. The cases developed severe tetanus with autonomic dysfunction. Pulmonary and gastrointestinal complications were common and the mortality rate was 25% [21]. In many countries, traditional practices continue to this day that carry a high risk for tetanus—practices such as scarification, circumcision, ear piercing and the application of oils, ghee and dung to the cut umbilical cord [37]. Clinical presentation The commonest presenting symptom is trismus. Rigidity progresses in a descending manner. Dysphagia, risus sardonicus and neck stiffness are soon followed by rigidity of the trunk and limbs. The spasms which follow may vary in severity and be localized or generalized, but tend to affect the trunk more than the limbs. Spasms may occur spontaneously or provoked by some form of stimulation. Arching of the trunk-opisthotonus is a feature of the established disease. Trismus develops to be a prominent feature, leading to considerable difficulty in feeding, maintaining oral hygiene and swallowing saliva. These difficulties often lead to aspiration bronchopneumonia—a frequent life-threatening complication. Neonatal tetanus presents most often on the seventh day of life with a short history of failure to feed. Spasms are typical but the diagnosis can be mistaken for meningitis and sepsis. Cephalic and localized tetanus are uncommon variants that may defy diagnosis for considerable periods. Cephalic tetanus [38,39] is a form that presents after wounding of the head and neck, in which trismus is often preceded by cranial nerve palsies: it accounts for 1–3% of the total number of reported cases and has a mortality of 15–30%. Localized tetanus accounts for a similarly small number of the reported cases. It has a long incubation period and manifestations, including flaccidity, restricted to muscles near the wound. The mechanism of the paralysis is not completely understood, but is likely to be related somehow to the inability of the toxin molecule to be conveyed to the central nervous system [40]. The spasms may spread from one limb to another (recruitment spasm). The signs may mimic other neurological disorders. The important clinical observation of autonomic dysfunction in tetanus was described first in the 1960s [41]. Autonomic dysfunction usually manifests itself as a hyperkinetic circulatory state with tachycardia and arrhythmias, increased stroke volume and increased cardiac index. These may be accompanied by depression of bowel motility and bladder dysfunction and episodes of sweating and pyrexia which may also indicate concurrent infection. These manifestations of sympathetic overactivity may alternate with episodes of hypotension from loss of systemic vascular resistance and bradycardia to the point of cardiac arrest from which resuscitation can be difficult. This has been attributed to sudden withdrawal of sympathetic activity rather than to an increase in parasympathetic activity because the response to atropine is variable. Other explanations for these episodes are catecholamine-induced myocardial damage, vagal stimulation and effects of the toxin on the brain stem that may impair baroreceptor function [42]. There may be complaints of abdominal pain amongst the presenting features and there is a report of a patient with Horner's syndrome and trismus from tetanus [43]. Diagnosis Early treatment is crucial to the chances of survival and recovery. The early diagnosis which enables early treatment must depend purely on clinical observation and may go by default in countries where the disease is uncommon. Tetanus may not come to mind because of the many variants from classical presentations. These can suggest a range of differential diagnoses including acute dental infections, acute tempero-mandibular disease, intracranial lesions, drug induced muscle dystonias and strychnine poisoning. These factors may delay the establishment of a definitive diagnosis [44]. Laboratory findings are virtually of no value except to rule out strychnine poisoning. Blood counts and blood chemical findings are unremarkable. Imaging studies of the head and spine reveal no abnormalities. The cerebrospinal fluid is normal and a lumbar puncture is not necessary. Recently a simple bedside test to diagnose tetanus has been described: the spatula test. A spatula is used to touch the posterior pharyngeal wall, and a positive test result is reflex spasm of the masseters. This occurred in 349 of 350 patients with tetanus (sensitivity 94%) and in no patient without tetanus (specificity 100%) [45]. Severity The severity of tetanus is usually predicted on the basis of the incubation period (time between injury and first symptom) and the onset time (time from first symptom to first spasm). Incubation periods of less than 14 days and onset periods of less than 48 h are said to herald a severe attack, though longer incubation periods and onset times do not guarantee a mild attack. A useful way of grading the severity of established symptoms for purposes of management and study is: Grade I—Trismus; Grade II—Dysphagia, neck rigidity, risus sardonicus, opisthotonus; Grade IIIa—Muscle rigidity, spasms; Grade IIIb—All of above and autonomic dysfunction. Treatment The principles of treatment once symptoms appear are: Eradication of the organism; Neutralization of toxin; Symptomatic treatment of the effects of the toxin; (3a) Control of muscle spasms and rigidity, (3b) Control of autonomic dysfunction; Supportive measures; Active immunization. Eradication of the organism Whatever the specific concerns about tetanus, ordinary clinical common sense dictates that any obvious wound must be cleaned and any devitalized tissue must be debrided, under general anaesthesia as necessary. It is, of course, also routine in all developed healthcare systems to attempt to establish or boost active immunity by giving tetanus toxoid as soon as possible after any at-risk injury. Metronidazole is the antibiotic of choice when there are specific concerns about tetanus because of its activity against anaerobes and effective penetration of devitalized tissues. Penicillin, the antibiotic of choice for decades, is a GABA antagonist and may aggravate the spasms of tetanus [46]. However, by the time symptoms present, the frequent absence of an obvious wound or tissue damage means that treatment based solely on adequate wound care is likely to be futile, and must not delay the more urgent attention that must be given to other measures, particularly neutralization of toxin. Neutralization of toxin. The importance of this measure is illustrated in experience documented by many hospitals. For instance, in a review of 2449 cases in 65 years at Charity Hospital, New Orleans, USA, the fatality rate in the pre antitoxin era (1840–1905) was 76.4%. From 1906 to 1923 the rate was 70% and, by 1966, it had dropped to 31.6%. However, in a review published in 1976, the mortality was 58% with a distinct change in the average age of patients from 25 years to 40 years and a virtual disappearance of neonatal tetanus over the period [47]. Neutralization of the toxin should be effected as early as possible after the appearance of symptoms attributable to tetanus, because the toxin becomes inaccessible to antitoxin after an indeterminate but usually relatively brief period [48]. Human tetanus immuno-globulin (HTIG) should be given intramuscularly (i.m.), preferably within 24 h of diagnosis. A dose of 500 units i.m. is now recommended in place of the larger traditional doses of 3000–5000 units. If HTIG is not available, equine antitetanus serum (ATS) is used after tests for hypersensitivity. Given i.m., neither type of antitoxin crosses the blood brain barrier, so these agents do no more than inactivate any circulating toxin. In attempts to inactivate the toxin bound to nerve tissue, equine ATS or HTIG have been given intrathecally, following Sherrington's pioneering studies [49]. Sanders et al. were amongst the earliest to report the benefit of intrathecal equine antitoxin [50] which reduced the mortality from 70 to 18%. Later intrathecal use of antitetanus serum was with steroids in an attempt to reduce adverse effects [51]. In a comparison in 1980, HTIG was given to 97 patients, at an intrathecal dose of 250 i.u. to 49 patients and an intramuscular dose of 1000 i.u. to the remaining 48: there were only three deteriorations (including one death) with the intrathecal administration but 15 deteriorations (including 10 deaths) with the intramuscular administration [52]. In neonatal tetanus, a meta analysis carried out by Abrutyn and Berin, failed to provide convincing evidence that intrathecal therapy with either equine ATS or HTIG is of major benefit, although clinically important treatment effects in some subgroups could not be excluded. They indicated the need for more definitive studies of the immediate and late complications of intrathecal therapy [53]. Symptomatic treatment Early treatment. Once dysphagia sets in, the development of spasms can be very rapid and there is a grave risk of aspiration. In one institution, patients are anaesthetized for tracheostomy and preparation for enteral feeding (by nasogastric tube, gastrostomy or jejunostomy) at the same time as wound debridement, so that they can then be nursed in a high dependency unit provided that spasms do not occur or recur [31]. Some institutions use endotracheal intubation to isolate the respiratory tract. Sedation and nursing in a quiet environment is essential and close observation is particularly necessary to anticipate the occurrence of spasms. Control of spasms. When spasms occur, breathing can be compromised by spasm of either the laryngeal or respiratory muscles. Frequent spasms lead to exhaustion and, because consciousness is not impaired, the patient is considerably distressed and anxious. Heavy sedation therefore becomes necessary and this often entails ventilatory support (see below). Diazepam has a traditional place and barbiturates are still widely used, at least in developing countries where there have been few opportunities to replace them with anything more novel. Benzodiazepine receptors are modulatory sites locked on the alpha subunits of GABA receptors, and in addition to producing sedation, benzodiazepines enhance the chloride-channel gating function of GABA by facilitating the binding of GABA to its receptors. Barbiturates decrease the rate of dissociation of GABA from its receptors. The enhanced opening of chloride channels leads to hyperpolarization of cell membranes making them more resistant to neuronal excitation. The usual dose of diazepam is 10–30 mg every 1 to 8 h, although a dose as high as 40 mg per h may be necessary. At high doses of diazepam, lactic acidosis can occur, though this is possibly attributable to its vehicle, propylene glycol. Chlorpromazine has been used for its sedative and (presumed) centrally mediated muscle relaxing properties. It also produces alpha-adrenergic blockade and depression of vasomotor reflexes mediated by the hypothalamus or brain stem. However, one of its main effects is the antagonism of dopamine as a neurotransmitter in the basal ganglia and limbic portions of the forebrain. Neuroleptic malignant syndrome has complicated tetanus treated with chlorpromazine [54]. The more traditional drugs, discussed above, produce prolonged effects which, in our experience, prolong the stay in intensive care—a facility which is in short supply in many developing countries. Midazolam has been used for prolonged sedation: the requirements very quite widely and, on occasions, its effects take 48–72 h to disappear after cessation of therapy [55,56]. Stevens et al. have described the use of isoflurane for sedation to facilitate controlled mechanical ventilation. Isoflurane was administered for 34 days, resulting in sustained serum concentrations of inorganic fluoride in excess of 50 μmol L−1 and a peak serum inorganic fluoride ion concentration of 87 μmol L−1. Although these concentrates are potentially nephrotoxic, no toxicity was evident clinically [57]. Propofol is another option for providing sedation particularly as therapeutic doses have been shown to potentiate GABA receptor mediated responses [58]. However, propofol is known to produce some degree of cardiovascular instability and this could cause further difficulties in the presence of autonomic disturbances which may occur during the course of the disease. But sedative agents, whether used alone or in combination, are often inadequate for the control of severe spasms and do not, in our experience, reduce the muscle rigidity sufficiently to allow mouth care and physiotherapy. Profound muscle relaxation is very often required, whether mediated centrally within the nervous system or more peripherally at the neuromuscular junction. Severe tetanus has been successfully treated with alternating infusions of propofol (20–80 mg h−1) and midazolam (5–15 mg h−1) for sedation and with vecuronium infusions for muscle relaxation. In this instance a continuous infusion of labetalol (10–20 mg h−1) was also used to control arterial blood pressure [59]. Mephenesin which produces skeletal muscle relaxation by an unknown mechanism in the central nervous system has been used in few instances. Sedation is not a prominent side effect [60]. Baclofen, a GABA agonist, diminishes transmission of monosynaptic extensor and polysynaptic flexor reflexes in the spinal cord. Its use has been reported recently in the management of tetanus. The effectiveness of repeated intrathecal injections of 500–1000 micrograms was assessed on the basis of resolution of contractures and paroxysms. The first injection was effective in nine out of 10 patients for 24–48 h. Haemodynamic effects were always acceptable, but five patients developed CNS depression with coma and respiratory insufficiency, three of them requiring artificial ventilation: in two of the latter, the breathing difficulties were later reversed by flumazenil. Five patients were treated exclusively with baclofen, of whom four ultimately recovered: of the five patients who had to be ventilated, only one ultimately recovered [61]. Baclofen has also been used by continuous intrathecal infusion [62]. The moves towards the use of GABA agonists is rational. In the early stages of tetanus when possibly only trismus and neck stiffness are present, GABA agonists may produce a beneficial modification of the clinical course of the disease. Dantrolene produces skeletal muscle relaxation without usually affecting the contractility of cardiac muscle or smooth muscle. It has a direct action on excitation-contraction coupling, presumably by decreasing the amount of calcium released from the sarcoplasmic reticulum, which indirectly prevents the activation of myosin ATPase and muscle contraction. In most instances dantrolene has been used with diazepam or midazolam as an adjunctive therapy. In one study in children, 4–6 mg kg−1 day−1 of dantrolene reduced the mortality from 73% in a control group to 33% in the dantrolene group [63]. Dantrolene obviated the need for neuromuscular blocking agents and mechanical ventilation in two patients with severe tetanus [64]. However, neuromuscular blocking agents are mainstay of treatment in the more severely affected cases. The choice of agent depends on personal preference within the limits of what is available. Pancuronium has fallen out of favour in some centres because of the possibility that its intrinsic sympathomimetic activity might aggravate the autonomic dysfunction. In the Third World, vecuronium an agent devoid of cardiovascular effects, has proved to be expensive. Atracurium has been used successfully with no cumulative effects [55]. Control of autonomic dysfunction Two different therapeutic approaches have been used in the management of sympathetic overactivity—central nervous system depression and peripheral adrenergic blockade. Traditionally alpha and beta adrenergic antagonists have been directed notionally at the more peripheral control of autonomic dysfunction. Propranolol and the combined alpha and beta antagonist labetalol have been incriminated in the occurrence of congestive cardiac failure, hypotension, bradycardia and cardiac arrests in some patients with tetanus. The short-acting beta adrenergic antagonist esmolol has been used on occasions, as has epidural blockade with a continuous lumbar epidural infusion of bupivacaine [66]. At least part of the beneficial effect of heavy sedation in suppressing autonomic dysfunction is by reducing catecholamine secretion. Central nervous system depression with thiopentone and general anaesthetics achieved a degree of success but prolonged use was limited by their potential toxicity [65]. Morphine has been found to be particularly effective—related possibly to the finding that the concentrations of endogenous opioids are low during 'crises'. The circulatory effects of morphine and other exogenous opiate agonists are complex, but the key feature is probably a depression of sympathetic outflow by actions at multiple sites in the CNS. Whatever the mechanisms, a mean daily dose of 103 (SD ± 36) mg of morphine produced useful reductions in mean arterial blood pressure and heart rate [67]. Clonidine has been used with varying success. It has been found to lower basal plasma catecholamine levels and had been successfully used in the treatment of autonomic epilepsy, a condition in which there is paroxysmal release of catecholamines, particularly of noradrenaline from nerve endings—just as in the autonomic disturbances of tetanus. Clonidine was followed by reductions in plasma noradrenaline concentrations, though not to within the normal range, and these were accompanied by a reduction in cardiovascular instability [68]. Magnesium given parenterally has a variety of actions that may be useful in tetanus. It is a potent sedative and muscle relaxant, it antagonizes calcium, blocks neuronal and adrenal catecholamine release and causes vasodilation. Magnesium sulphate has an established place in the management of pre-eclampsia and has been used successfully to control cardiovascular disturbances during delivery in pregnant women with phaeochromocytoma [69]. There are reports of its successful use to control autonomic dysfunction in tetanus and it has been considered a useful adjunct to sedation, paralysis and ventilation [70]. One of us (DA) has used magnesium sulphate titrating the dose against suppression of spasms and the preservation of the patellar reflex (a clinical indicator of the serum levels of magnesium). Useful control of spasms was achieved at serum magnesium levels which did not compromise ventilation. Cardiovascular stability without the need for sedation was a clinically important observation. Supportive treatment. Sykes [71], working in Durban in the early 1960s, introduced the concept of muscle paralysis and ventilatory care in the management of tetanus. This reduced the mortality from 80 to 40% and later to 10–20%. This was a landmark, not only for the treatment of tetanus, but for the overall development of the concept of intensive care from one restricted to the provision merely of ventilatory support towards one directed at supporting all organ systems that were dysfunctional. Thus in tetanus, not only are there possible dysfunctions of ventilation (from the disease and its required treatment) and pulmonary gas exchange (from aspiration of oral and gastrointestinal contents), but there is also the autonomic dysfunction that is a recognized part of the disease as well as the now recognized threats from immobility (thromboembolism), fluid retention from inappropriate secretion of antidiuretic hormone and nosocomial infections from prolonged invasive instrumentation. There has been much dispute as to whether an endotracheal tube or a tracheostomy should be used to secure control of the airway in patients requ