Unforgettable tetanus

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. 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The of this is in by many in a of cases in years at USA, the rate in the antitoxin was to the rate was and, by it to However, in a published in the mortality was with a in the of patients from years to years and a of neonatal tetanus over the period of the toxin should be as as after the of symptoms to because the toxin to antitoxin after an but usually period tetanus should be within of A of is now in of the of is not is used after for of antitoxin the blood brain so no more than any toxin. 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It is a potent and muscle it blocks and adrenal release and has an in the management of and has been used to in with phaeochromocytoma There are of its to autonomic dysfunction in tetanus and it has been considered a to and of has used the of spasms and the of the clinical of the of of spasms was at which not the for was a treatment. in in the the of muscle and in the management of tetanus. This reduced the mortality from to and later to This was a not only for the of but for the overall of the of from one to the of one at systems that were Thus in not only are there of the disease and its and of and but there is also the autonomic dysfunction that is a recognized part of the disease as well as the now recognized from from of hormone and infections from There has been as to an or a should be used to of the in patients for tetanus. 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