NEUROLOGICAL ASPECTS OF TROPICAL DISEASE

Tetanus

J J Farrar, L M Yen, T Cook, N Fairweather, N Binh, J Parry, C M Parry

General descriptionTetanus was first described in Egypt over 3000years ago and was prevalent throughout theancient world. Despite the availability ofpassive immunisation since 1893 and an eVec-tive active vaccination since 1923, tetanusremains a major health problem in thedeveloping world and is still encountered in thedeveloped world. There are between 800 000and 1 million deaths due to tetanus each year,of which about 400 000 are due to neonataltetanus.1 Eighty per cent of these deaths occurin Africa and south east Asia and it remainsendemic in 90 countries world wide.2 Incom-plete vaccine deployment among the popula-tion at risk is the major factor, but the quality ofthe tetanus toxoid and how it is stored is alsoimportant. Fifteen lots, in use from eightmanufacturers in seven countries, had potencyvalues below World Health Organisation(WHO) requirements.1

In this decade 12–15 cases have beenreported per year in Britain3 and between40–60 in the United States.4 5 Mortality varieswith patients’ age. In the United Statesmortality in adults younger than 30 may be aslow as zero. However, in those aged over 60,who account for 75% of tetanus deaths,mortality is above 50%.4–6 In Portugal between1986 and 1990 all age mortality varied between32% and 59%.7 In neonatal cases mortalitywithout ventilation was reported as 82% in1960 and 63%-79% in 1991.8 9 With ventila-tion this may be reduced to as low as 11%.10

The facilities available to manage severetetanus have a major impact on the therapeuticoptions and mortality. In the United Kingdomintensive care costs $1500–2500/patient/day;such costs are clearly unrealistic in most of theworld where tetanus is a major problem.11

Without the facility to artificially ventilatepatients, airways obstruction, respiratory fail-ure, and renal failure are the major contribu-tory factors. Availability of artificial ventilationshould prevent most deaths caused directly byacute respiratory failure even in very severecases. However, autonomic disturbances thenbecome a major problem. Sudden cardiacdeath and the complications of prolonged criti-cal illness (nosocomial infections, particularlyventilator associated pneumonia, generalisedsepsis, thromboembolism, and gastrointestinalhaemorrhage) become the major causes ofdeath. The clinical course of tetanus is oftenunpredictable and patients should be closelymonitored throughout their illness.

Causative agent: Clostridium tetaniThe clostridia genus is a diverse group ofanaerobic spore forming gram positive bacilli.They are widely distributed in the environ-ment, and are found in the intestinal flora ofdomestic animals, horses, chickens, and hu-mans. Endospores are produced which arewider than the bacillus, giving rise to the char-acteristic drumstick shape (fig 1). The mostnoteworthy toxin mediated diseases associatedwith infection by this genus are tetanus (Ctetani), and botulism (C botulinum). C tetani is agram positive, obligate anaerobic bacillus,older organisms lose their flagella after thedevelopment of a spore.12 The spores areextremely stable, and although boiling for 15minutes kills most, some will survive unlessautoclaved at 120°C, 1.5 bar, for 15 minutes,which ensures sterility.

In routine practice few attempts are made toculture C tetani; it is diYcult to culture, a posi-tive result does not indicate whether the organ-ism contains the toxin producing plasmid, andC tetani may be present without disease inpatients with protective immunity. There isvery little recent information on the antimicro-bial sensitivity of C tetani. Similarly, there havebeen very few attempts to quantify the toxinload and assess the prognostic relevance of this.If large amounts are produced the toxin may betransported by blood and the lymphatics aswell as by direct entry into nerve fibres, hencemore rapid and wider dissemination of theeVects of the toxin. Tiny amounts of the toxinare thought to be present in a typical infection.Rethy and Rethy estimated the human lethaldose to be approximately 500 pg/kg—that is,25 ng/70 kg adult.13

Tetanus toxin and pathogenesisThe toxin gene is encoded on a 75 kb plasmidand synthesised as a single polypeptide with amolecular weight of 150 000. The completeamino acid sequence of the toxin is knownfrom gene cloning.14–16 The polypeptide under-goes post-translational cleavage into two di-sulfide linked fragments, the light (L) andheavy (H) chains (fig 2). The carboxyl terminalportion of the H chain, termed HC, mediatesattachment to gangliosides (GD1b and GT1b) onperipheral nerves, and subsequently the toxin isinternalised.17 It is then moved from theperipheral to the central nervous system byretrograde axonal transport and trans-synapticspread. The entire toxin molecule is internal-ised into presynaptic cells and, in a process

J Neurol Neurosurg Psychiatry 2000;69:292–301292

Wellcome TrustClinical ResearchUnit, Centre forTropical Diseases, ChoQuan Hospital, 190Ben Ham Tu, District5, Ho Chi Minh City,VietnamJ J FarrarJ ParryC M Parry

Centre for TropicalMedicine, NuYeldDepartment of ClinicalMedicine, JohnRadcliVe Hospital,Oxford, UKJ J FarrarJ ParryC M Parry

Centre for TropicalDiseases, Cho QuanHospital, 190 Ben HamTu, District 5, Ho ChiMinh City, VietnamL M YenN Binh

Department ofAnaesthetics, RoyalUnited Hospital, Bath,United KingdomT Cook

The Department ofBiochemistry,Imperial College ofScience, Technologyand Medicine, LondonSW7 2AZ, UnitedKingdomN Fairweather

Correspondence to:Dr Jeremy Farrarjeremyjf@hcm.vnn.vn

Received 21 September 1999and in revised form9 November 1999Accepted 26 November 1999

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requiring the HN fragment, the L chain isreleased from the endosome. The L chain is azinc metalloprotease, which cleavessynaptobrevin.18 A single base pair mutation inthe light chain abolishes this proteolyticactivity.19 Synaptobrevin is an integral mem-brane component of synaptic vesicles and isessential for the fusion of synaptic vesicles withthe presynaptic membrane. Cleavage bytetanus toxin L chain prevents release of theircontents, the inhibitory neurotransmitterã-aminobutyric acid (GABA), into the synapticcleft. The á motor neurons are therefore underno inhibitory control and undergo sustainedexcitatory discharge causing the characteristicmotor spasms of tetanus. The toxin exerts itseVects on the spinal cord, the brain stem,peripheral nerves, at neuromuscular junctions,and directly on muscles. To what extent corti-cal and subcortical structures are involvedremains unknown. Certainly the toxin is apotent convulsant when injected into thecortex of experimental animals.

Tetanus toxin is highly homologous in aminoacid sequence to the family of botulinum neu-rotoxins, which like tetanus toxin, inhibit neu-rotransmitter release by cleavage of proteinsinvolved in vesicle fusion.20 The distinct diVer-

ence in clinical symptoms between botulismand tetanus is due to the location of toxinaction. Botulinum toxin is not transported tothe CNS and remains at the periphery where itinhibits the release of acetycholine. This resultsin an acute flaccid paralysis.

x Ray crystallographic studies have shownthe three dimensional structure of the tetanustoxin HC chain responsible for binding ofgangliosides.21 The HC fragment, which canundergo retrograde transport in the absence ofthe remainder of the toxin molecule, iscomposed of two dissimilar structural domains(fig 3). These domains, which in other systemsare involved in recognition of saccharides andproteins respectively, exhibit structural homol-ogy to legume lectins and to proteins such asinterleukin (IL)-1á and IL-1â and may reflectthe ability of the HC fragment to bind to recep-tors. Reflecting high sequence homology, theoverall three dimensional structure of tetanustoxin HC is remarkably similar to HC of botuli-num toxin A.22 Thus the binding and transportactivities of these two toxin families, which leadto distinct clinical symptoms, could be due tosubtle diVerences in sequence within the HC

chains, which result in binding to distinctreceptors. Site directed mutagenesis of the Hc

Figure 1 Acridine orange stain of characteristic C tetani with endospores wider than the characteristic drumstick shape.

Figure 2 Linear representation of tetanus toxin showing the functions of the L, HN, and HC chains. Each chain is 50 kDa.

NH2 S– COO

• Immunogenic• Neuronal cellbinding• Gangliosidebinding• Retrogradetransport

• Endosome• Zn2+ dependentprotease• Cleavage ofsynaptobrevin

L HN HC

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domain will help to clarify the role of individualresidues in binding and transport. In additionto a ganglioside receptor, a protein receptor fortetanus toxin has been hypothesised, but nonehas yet been identified.

Clinical features and managementTetanus typically follows deep penetratingwounds where anaerobic bacterial growth isfacilitated. The most common portals of infec-tion are wounds on the lower limbs, postpar-tum or postabortion infections of the uterus,non-sterile intramuscular injections, and com-pound fractures. However, even minor traumacan lead to disease and in up to 30% of patientsno portal of entry is apparent.23 Tetanus hasbeen reported after a myriad of injuries,including intravenous and intramuscular injec-tions, acupuncture, earpiercing, and even fromtoothpicks. It can follow from chronic infec-tions such as otitis media,24 25 and has beenreported via a decubitus ulcer.26 Tetanusacquired after intramuscular injection withquinine is associated with a higher mortalitythan other modes of acquisition.27

The incubation period (the time frominoculation to the first symptom) can be as

short as 24 hours or as long as many monthsafter inoculation with C tetani. This interval is areflection of the distance the toxin must travelwithin the nervous system, and may be relatedto the quantity of toxin released. The period ofonset is the time between the first symptomand the start of spasms. These periods areimportant prognostically, the shorter the incu-bation period or period of onset the moresevere the disease. Trismus (lockjaw)—theinability to open the mouth fully owing torigidity of the masseters—is often the firstsymptom. Tetanus can be localised at the site ofinjury causing local rigidity and pain. Thisform generally has a low mortality. However,when local tetanus occurs from head and facialinjuries cephalic tetanus can develop, which isa local variant but has a higher mortality. Gen-eralised tetanus is the most common form ofthe disease, and presents with pain, headache,stiVness, rigidity, opisthtonus, and spasms,which can lead to laryngeal obstruction. Thesemay be induced by minor stimuli such as noise,touch, or by simple medical and nursingprocedures such as intravenous and intramus-cular injections, suction, or catheterisation.The spasms are excruciatingly painful and maybe uncontrollable leading to respiratory arrestand death. Spasms are most prominent in thefirst 2 weeks, autonomic disturbance usuallystarts some days after spasms and reaches apeak during the second week of the disease.Rigidity may last beyond the duration of bothspasms and autonomic disturbance. Severerigidity and muscle spasm necessitates paraly-sis for prolonged periods in severe tetanus.

Some groups have attempted to devise scor-ing systems to assess prognosis; the Phillipsscore and the Dakar score (tables 1 and 2) aretwo examples.28 29 Both these scoring systemsare relatively straightforward schemes whichtake into account the incubation period and theperiod of onset as well as neurological and car-diac manifestations. The Phillips score alsofactors in the state of immune protection. The

Figure 3 Three dimensional crystal structure of the Hc chain showing the two structuraldomains. Green and red ribbons correspond to â sheet and á helical regions respectively.

Table 1 Prognostic scoring systems in tetanus: Dakar score

Prognostic factor

Dakar score

Score 1 Score 0

Incubation period <7 days >7 days or unknownPeriod of onset <2 days >2 daysEntry site Umbilicus, burn, uterine, open fracture,

surgical wound, intramuscular injection All others plus unknownSpasms Present AbsentFever >38.4°C <38.4°CTachycardia Adult>120 beats/min Adult<120 beats/min

Neonate>150 beats/min Neonate<150 beats/minTotal score

Table 2 Prognostic scoring systems in tetanus: Phillips score

Factor Score

Incubation time:<48 hours 52–5 days 45–10 days 310–14 days 2>14 days 1

Site of infection:Internal and umbilical 5Head, neck, and body wall 4Peripheral proximal 3Peripheral distal 2Unknown 1

State of protection:None 10Possibly some or maternal immunisation inneonatal patients

8

Protected >10 years ago 4Protected <10 years ago 2Complete protection 0

Complicating factors:Injury or life threatening illness 10Severe injury or illness not immediately lifethreatening

8

Injury or non-life threatening illness 4Minor injury or illness 2ASA Grade 1 0

Total score

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more clinical grading system developed byUdwadia is also useful.30

The diagnosis is a clinical one, relativelyeasy to make in areas where tetanus is seenoften, but often delayed in the developedworld where cases are seen infrequently.31 ThediVerential includes tetany, strychnine poison-ing, drug induced dystonic reactions, rabies,and orofacial infection. In neonates the diVer-ential diagnosis would also include hypo-calcaemia, hypoglycaemia, meningitis andmeningoencephalitis, and seizures.

Penicillin remains the standard therapy fortetanus in most parts of the world, althoughantibiotics for Clostridium tetani probably play arelatively minor part in the specific treatment ofthe disease. The dose is 100 000–200 000IU/kg/day intramuscularly or intravenously for7 to 10 days. Johnson and Walker were the firstto report that intravenous administration ofpenicillin could cause convulsions, and went onto show, in animal models, that penicillincaused myoclonic convulsions when applieddirectly to the cortex.32 Penicillin became thestandard model for induction of experimentalfocal epilepsy. The structure of penicillin,distant to the â-lactam ring is similar toã-aminobutyric acid (GABA) the principalinhibitory neurotransmitter in the CNS. Peni-cillin therefore acts as a competitive antagonistto GABA. Penicillin does not readily cross theblood-brain barrier, but in high cumulativedoses it can cause CNS hyperexcitability. Intetanus this side eVect of penicillin could syner-gise with the action of the toxin in blockingtransmitter release at GABA neurons.

Metronidazole is a safe alternative, and maynow be considered as the first line therapy.After rectal administration metronidazole israpidly bioavailable and causes fewer spasmsthan repeated intravenous or intramuscularinjections. Ahmadsyah and Salim were the firstto compare penicillin and metronidazole, andshowed a reduction in mortality in themetronidazole group (7% compared with24%).33 In a much larger study Yen et alrecruited over 1000 patients and showed thatthere was no significant diVerence in mortalitybetween the penicillin and metronidazolegroup.34 However, the 533 patients randomisedto metronidazole required fewer muscle relax-ants and sedatives compared with 572 patientsrandomised to penicillin. This may be ex-plained by the action of penicillin at GABAer-gic synapses and may therefore apply to thethird generation cephalosporins. The structureof these drugs is similar to that of penicillin andceftazidime has been shown to induce absenceseizures with spike and wave discharges.35 Ifmetronidazole is available and applicable thisshould be considered as the drug of choice inthe treatment of tetanus. The dose is 400 mgrectally every 6 hours, or 500 mg every 6 hoursintravenously for 7–10 days. Erythromycin,tetracycline, vancomycin, clindamycin, doxycy-cline, and chloramphenicol would be alterna-tives to penicillin and metronidazole if thesewere unavailable or unusable in individualpatients.36 37 There is little or no indication forthe use of other antibiotics in the management

of tetanus. There is a need for an up to dateassessment of the antimicrobial sensitivitypatterns of clinical isolates of C tetani.

Pyridoxine (vitamin B6) is a coenzyme withglutamate decarboxylase in the production ofGABA from glutamic acid, and increasesGABA concentrations in animal models. In anunblinded open trial 20 neonates with tetanuswere treated with pyridoxine (100 mg/day) andcompared with retrospective records. Themortality in the pyridoxine treated group wasreduced.38 The role of pyridoxine in themanagement of neonatal tetanus should bere-examined in a blind randomised trial.

The evidence for a role of steroids is notconvincing. They have been reported to be ofbenefit in tetanus; however, as is often the casein studies on this disease the trials have notrecruited enough patients to be convincing orhave been inadequately controlled. In twostudies betamethasone has been shown toreduce the mortality, but only a few patientswere studied.39–41 Steroids should not berecommended in the management of tetanusunless further blinded controlled studies areconducted in large enough numbers to showsignificant diVerences.

Respiratory failure is the commonest directcause of death from tetanus in the developingworld, particularly when artificial ventilationmay not be available for every case. Where it isavailable attempts should be made to anticipateand detect patients at risk from hypoxia andairways obstruction, aspiration hypoventila-tion, pneumonia, and respiratory arrest. Earlyairways protection and ventilatory support isoften needed. The eVects of diVerent modes ofassisted ventilation in tetanus have not beenevaluated. The modes used will often belimited by the complexity of the ventilatorsavailable in the intensive care unit. Those areaswith many cases are likely to be those withrudimentary equipment. In the early stages ofthe disease when rigidity and spasm are promi-nent muscular paralysis and controlled manda-tory ventilation are necessary. Poor complianceand oxygenation due to muscular rigidity orpulmonary complications may be overcome bya combination of pressure controlled ventila-tion and positive end expiratory pressure(PEEP). In the later stages of the diseasemodes of ventilation that allow spontaneousventilation (synchronised intermittent manda-tory, continuous positive airway pressure andbiphasic positive airway pressure ventilation)are generally preferred and may optimise therespiratory pattern, reduce sedation require-ments, minimise muscle wastage, and reducethe likelihood of acquired critical illnessneuropathy or myopathy. However, there is lit-tle evidence base in tetanus for these advancedmodes of support.

Percutaneous tracheostomy is now a routinetechnique on many intensive care units. It isparticularly suitable for patients with tetanus.Patient transfer to and from an operatingtheatre (entailing unnecessary stimulation) isavoided. Other potential advantages overtraditional open surgical techniques includereduced blood loss, reduced operative

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morbidity and reduced long term sequelae.42 43

The single step forceps dilatational method israpid and can be used for emergency airwaymanagement and the serial dilation techniqueis useful for intubated patients requiringtracheostomy.44–46

Traditionally the long acting agent pancuro-nium has been used for muscular paralysis.Pancuronium is an inhibitor of catecholaminereuptake and as such could worsen autonomicinstability in severely aVected patients. Therehave been isolated reports of worsening hyper-tension and tachycardia associated with its usein tetanus.47 Alternatives include the olderagents d-tubocurarine and alcuronium whichhave been reported to reduce haemodynamicinstability, but may also be a cause of hypoten-sion through histamine release. Vecuroniumhas been proposed as it is “cardiovascularlyclean” but is relatively short acting.48 Longeracting agents are preferable as they lend them-selves to administration by intermittent bolusrather than requiring infusion. Of the neweragents pipercuronium and rocuronium arelong acting and “clean” but are expensivecompared with older drugs. Individual drugshave not been compared in randomised trials.The directly acting muscle relaxant dantrolenehas been reported in one case in which spasmswere diYcult to control. Paralysis was unneces-sary after administration of dantrolene, spasmsreduced, and patient condition improved.49

The sedative agent propofol may also have use-ful muscle relaxant properties. Sedation withpropofol allowed control of spasms and rigiditywithout additional relaxant. Examination ofEMG and neuromuscular function duringpropofol boluses showed an 80% reduction inEMG activity without alteration of neuromusc-ular function. However, drug concentrationswere closer to anaesthetic than sedative dosesand mechanical ventilation would berequired.50 51

Autonomic disturbance with sustained labilehypertension, tachycardia, vasoconstriction,and sweating is common in severe cases.Profound bradycardia and hypotension mayoccur and may be recurrent or preterminalevents. Involvement of the sympathetic nervoussystem was recognised in 1968.52 Sedation,which is useful for controlling spasms andrigidity, is also the first step in reducingautonomic instability. Benzodiazepines aug-ment GABA agonism by inhibiting an endog-enous inhibitor at the GABAA receptor. Ad-equate sedation is essential in tetanus but is adouble edged sword. Benzodiazepines are themost commonly used sedative agents. Di-azepam has a wide margin of safety, has a rapidonset of action, can be given orally, rectally, orintravenously, and is a sedative, an anticonvul-sant, and a muscle relaxant. It is also cheap andavailable in most parts of the world. However,it has a long cumulative half life (72 hours) andhas active metabolites, in particular oxazepamand demethyldiazepam. Invariably, in the dosesrequired to achieve adequate control of spasms(often up to 3–8 mg/kg/day in adults) respira-tory depression, coma, and medullary depres-sion are common. Establishing the correct

therapeutic window is extremely diYcult,particularly in patients requiring prolongedsupport. Midazolam is an alternative, but it isusually not available or not aVordable inregions where tetanus is seen often.53 54

Phenothiazines, particularly chlorpro-mazine, are useful sedatives with á-adrenergicand anticholinergic eVects. Phenobarbital hasbeen widely used since the 1960s.55 Morphineis particularly eVective as sedation and cardio-vascular stability may be achieved withoutcompromising cardiac performance. Importantactions in reducing cardiovascular instabilityinclude replacing depleted endogenous opioidsand histamine release.56–59 With all these drugsenormous doses may be required.

Basal catecholamine concentrations rise butnoradrenaline (norepinephrine) rises moremarkedly than adrenaline (epinephrine). Nor-adrenaline concentrations may rise 10-fold,spontaneously or in response to stimulation,leading to a “sympathetic storm”.60 61 Theserises are similar to those found in phaeochro-mocytoma. Sympathetic neuronal overactivityis generally more prominent than adrenalmedullary overactivity and hypertension isaccompanied by a rise in systemic vascularresistance without large changes in cardiacindex.62 63 Histological changes in the hearts ofpatients dying from tetanus are strikingly simi-lar to those of patients with phaeochromocy-toma and the likely cause in both is persistentlyraised concentrations of catecholamines.64

Early attempts to control autonomic distur-bance included â and á-adrenoceptor blockersand combined block either with propanololand betanidine or labetolol.65 66 Mortality wasnot markedly reduced by this treatment andconcerns about â blockade and sudden deathhave been raised.67 Sudden falls in catecho-lamine concentrations after “sympatheticstorms”, catecholamine induced cardiac dam-age, negative inotropism, â-blocker inducedvasoconstriction, and unopposed parasympa-thetic activity are all plausible mechanisms.Esmolol, an ultrashort acting â-blocker, mayhave advantages over other â-blockers and itssuccessful use has been reported.69 However, itis expensive ($450/day) and catecholamineconcentrations remain increased.68

Other reported treatments for the autonomicdisturbance in tetanus include atropine, cloni-dine, and spinal bupivaccaine. Unfortunatelymost reports are either case reports or smallseries and there are few trials that are designedto compare treatments or examine outcomemeasures adequately. There have been reportsof successful management of autonomic distur-bance with intravenous atropine.69 Doses of upto 100 mg/h were used in four patients. Theauthors argued that tetanus is a disease of ace-tylcholine excess and used these high doses toachieve muscarinic and nicotinic blockadeproviding autonomic blockade, neuromuscularblockade, and central sedation. Blockade of theparasympathetic nervous system was reportedto markedly reduce secretions and sweating.Oral or parenteral clonidine has been used withvariable success. In one report of 27 patientstreated over 12 years, the group randomised to

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receive clonidine had a significantly lowermortality.70 71 Epidural or spinal bupivacainehave also been reported to improve haemody-namic instability.72–74 Unfortunately, most re-ports are either case reports or small series andthere are few adequate trials that have com-pared treatments or examined important out-come data.

Intrathecal baclofen (a GABAB agonist) hasbeen reported in some small series with varyingsuccess.75 Doses have ranged from 500 to 2000mg/day and have been given as boluses or infu-sion. Larger doses and boluses are associatedwith more side eVects.76 In all reports a signifi-cant number of patients developed coma andrespiratory depression necessitating ventila-tion. In some cases adverse eVects were revers-ible with the GABAA antagonist flumazenil, butthis is not reliable. The technique is invasive,costly, and facilities for ventilation must beavailable immediately. Tetanus patients are atrisk of sepsis and may require anticoagulationwhich makes repeated or continuous spinaltechniques a significant risk.

Magnesium sulphate has been used both inventilated patients to reduce autonomic distur-bance and in non-ventilated patients to controlspasms.56 77 78 Magnesium is a presynapticneuromuscular blocker, blocks catecholaminerelease from nerves and adrenal medulla,reduces receptor responsiveness to releasedcatecholamines, and is an anticonvulsant and avasodilator. It antagonises calcium in the myo-cardium and at the neuromuscular junctionand inhibits parathyroid hormone release solowering serum calcium. In overdose it causesparalysis and probably sedation or anaesthesia,although this is controversial.79–81 In the paperby James and Manson, patients with verysevere tetanus were studied and magnesiumwas found to be inadequate alone as a sedativerelaxant but an eVective adjunct in controllingautonomic disturbance.56 Serum concentra-tions were diYcult to predict and regularmonitoring of serum magnesium and calciumconcentrations were required. Muscular weak-ness was readily apparent and ventilation wasrequired in all cases. Attagyle and Rodrigostudied patients at an earlier stage of the illnessyet all cases were probably severe.78 They usedsimilar doses of magnesium to try to avoidsedatives and positive pressure ventilation andreported successful control of spasms and con-trol of rigidity. Magnesium concentrationswere predictable and readily kept within thetherapeutic range by using the clinical signs ofthe presence of a patella tendon reflex. In bothstudies the absence of hypotension and brady-cardia was by contrast with results with âblockade. Both groups agreed that tidal volumeand cough may be impaired and secretionsincreased: tracheostomy is mandatory andventilatory support must be readilyavailable.56 80 More work is necessary to definethe role of magnesium both with regard to thephysiological eVect it exerts on neuromuscularfunction in the presence of tetanus andsecondly to establish what role if any it has inthe routine management of severe tetanus.

In patients with a deep wound thoroughdebridement and toilet are critical to reducethe anaerobic conditions that bacteria thrive in.

The common complications in tetanus, suchas nosocomial infection, bed sores, trachealstenosis, and gastrointestinal haemorrhage, areoften attributable to prolonged periods ofimmobility, critical illness, and intensive care.Tracheal stenosis can be a problem in children,although it is probably underreported inadults. Secondary infections are a frequentcomplication, most commonly associated withthe lower respiratory tract, urinary catheterisa-tion, and wound sepsis. Attempts must bemade to prevent secondary infection and muchis achieved by attention to detail in basic care.Maintaining adequate spacing between bedsand general standards of cleanliness such asregular hand washing by staV and visitors aresimple eVective measures.82 Tracheostomy sitecleaning, strict sterile technique during tra-cheal suction, and basic care of peripheral orcentral venous access sites and the urinarycatheter are all fundamental to good treatment.Respiratory complications from aspiration andhypoventilation are common and may bereduced by early tracheostomy, avoiding na-sogastric tubes where possible, and nursingpatients in a 15°-30° sitting up position. Gramnegative organisms, particularly Klebsiella andPseudomonas are common, and staphylococcalinfections are also often encountered.

Meticulous mouth care, chest physiotherapy,and regular tracheal suction are essential toprevent atelectasis, lobar collapse, and pneu-monia particularly as salivation and bronchialsecretions are greatly increased in severetetanus. Adequate sedation is mandatory be-fore such interventions in patients at risk ofuncontrolled spasms or autonomic disturbanceand the balance between physiotherapy andsedation may be diYcult to achieve.

Energy demands in tetanus may be very highdue to muscular contractions, excessive sweat-ing, and sepsis. Weight loss is a universal find-ing and nutrition is of great importance.Enteral feeding should be established as earlyas possible. Enteral feeding has advantages overparenteral feeding as it maintains gastro-intestinal integrity and reduces respiratory andgeneralised septic complications.83 When facili-ties allow, percutaneous endoscopic gastros-tomy may be established, so avoiding thestimulation and reflux associated with anasogastric tube. In those patients unable totolerate enteral feeding cytoprotection is bestachieved with sucralfate or ranitidine.84 85

Measures to avoid serious thromboemboliccomplications include compression stockings,subcutaneous heparin, and limb physiotherapy.

There is very little information on follow upof patients after tetanus, particularly for cogni-tive function. In one of the few studies toexamine this question, Anlar et al foundenuresis, mental retardation, and growth delayto be frequent sequaelae after neonataltetanus.86 This is an area of clinical research intetanus which deserves further attention.

The clinical features, admission severityscores, and outcomes from 500 consecutive

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patients admitted to the Tetanus Unit at theCentre for Tropical Diseases in Ho Chi MinhCity are outlined in table 3.

VaccinationPassive immunisation with human or equinetetanus immunoglobulin shortens the courseand may reduce the severity of tetanus. Thehuman antiserum is isolated from a pool ofplasma derived from healthy human tetanusimmune donors, and has a half life of24.5–31.5 days. The equine (or bovine) form,widely available throughout the developingworld, has a higher incidence of anaphylacticreactions and a half life of only 2 days, but ismuch cheaper to produce. If available humanantiserum should be administered but in mostparts of the world equine antitoxin is thestandard.

In established cases patients should receive500–1000 IU/kg equine antitoxin intrave-nously or intramuscularly. Anaphylactic reac-tions occur in 20% of cases, in 1% they aresevere enough to warrant adrenaline, antihista-mines, steroids, and intravenous fluids. If avail-able 5000–8000 IU human antitetanus immu-noglobulin should be given intramuscularly;this has a lower incidence of side eVects.Antitetanus toxin was first used in 1893, andthere was a dramatic fall in the incidence ofdisease among soldiers in the first world afterits introduction. Although the antiserum willhave an eVect only on circulating and unboundtoxin (demonstrated in serum samples of only10% of cases at presentation and in 4% of CSFsamples, it should be administered to allpatients with tetanus.87 Whether it should alsobe infiltrated locally at the portal of entry isunclear and should be examined prospectively.For prophylaxis 1500–3000 IU equine or 250–500 IU human antitetanus immunoglobulinshould be given.

Passive immunisation should be adminis-tered as soon as possible after the injury, once

the toxin is bound and internalised it willclearly have no eVect. The blood concentrationof passive antitoxin to protect a human againsttetanus is approximately 0.1 IU/ml. When3000 IU are administered intramuscularlymaximum concentrations are reached in 24–48hours and adequate concentrations are main-tained for 10–15 days. It is not easy to assessthe optimal dose of antiserum to give forprophylaxis. Extrapolation from animal workwould suggest that these doses are too low andthat 50 000 IU would aVord greater protection;however, at such doses the incidence of sideeVects is higher. The side eVects can be eitheracute anaphylactic reactions or delayed serumsickness. The incidence of immediate reactionscan be reduced by simultaneous (or 15 minutesbefore use) injection with an antihistamine(promethazine). The use of the Besredka rapiddesensitisation method does not necessarilyprevent anaphylactic reactions. The use ofhuman tetanus immunoglobulin is very rarelyassociated with anaphylactic reactions, createsa longer duration of protective immunity, andlower doses can be used (500–1000 IU). It isthe passive immunisation of choice; unfortu-nately it remains unaVordable in many parts ofthe world.

Complete human immunoglobulin now canbe engineered in vitro and designed for specificantigens.88 This raises the possibility of produc-ing human antibodies specific for the tetanustoxin, free from the risks of infection, easy tostore, and potentially available at a cost aVord-able in the developing world. Owing to itssmaller size it is possible that the antigen bind-ing domain of the immunoglobulin, the Fabfragment, may gain better access to the toxin,and so enhance neutralisation. Fab fragmentscan be produced from donors, but theengineered approach to antibody productionwould facilitate this.

Intrathecal therapy with antitetanus serumhas been subjected to clinical trials. A meta-analysis has concluded that there is currentlyno evidence of a beneficial eVect in neonates oradults using equine or human tetanus immuneglobulin, and that the safety of their useintrathecally remains unproved.89

In addition to passive immunisation, activevaccination needs to be administered to allpatients, so called active-passive immunisation.This adds to the short term immunity (pas-sive), and to long term humoral and cellularimmunity (active). As the first is declining thesecond appears and thus avoids a window ofnon-protection. From experimental work inanimals it is clear that the toxoid starts acting afew hours after injection and before a humoralresponse is detectable. Presumably the toxoidsaturates the ganglioside receptors and pre-vents wild type toxin binding. The toxoid andthe human (or equine) antitetanus immu-noglobulin should be administered at diVerentsites on the body to prevent interaction at theinjection site. If both are to be administeredtogether no more than 1000 IU human or 5000IU equine antitetanus immunoglobulin shouldbe administered, higher doses can neutralisethe immunogenicity of the toxoid.

Table 3 Five hundred consecutive patients with tetanus: Centre for Tropical Diseases, HoChi Minh City

Demographic:500 Consecutive non-neonatal patients admitted between May 1997 and February 1999.343 Male 157 FemaleAge<15 years 18.8%Age>65 years 12.2%39 Neonates were admitted in the same time periodMortality in non-neonates 19%Mortality in neonates 45%

Entry site:Lower limb 53.3% Head 10.4%.Upper limb 10.8% Injections 1.8%.Unknown: 22.2%.

Incubation period Median (range) 9.5 days (1–60)Time to first symptom Median (range) 3 days (1–92)Period of onset Median (range) 48 hours (0–264)Symptoms on admission:

Lockjaw 96% Spasms 41%Back pain 94% Sweating 10%Muscle stiVness 94% DiYculty breathing 10%Dysphagia 83% Fever 7%

Admission severity scores and mortality rates:Dakar score Mortality Phillips score Mortality>3 35/59 (59%). >17 58/170 (34%).<3 60/440 (14%). <17 38/330 (11%).RR 4.35 (3.17–5.97) RR 2.96 (2.06–4.27)

By combining the Dakar and Phillips scores in individual patients:Dakar >3 and Phillips >17 compared with Dakar <3 and Phillips <17RR 3.68 (2.49–5.45)

RR = Relative risk.

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Tetanus toxoid for vaccination is producedby formaldehyde treatment of the toxin and itsimmunogenicity is improved by absorptionwith aluminium hydroxide. Alum absorbedtetanus toxoid is very eVective at preventingtetanus with a failure rate of 4/100 millionimmunocompetent people. In the UnitedKingdom and United States it is administeredto children between 2–6 months (three doses at4 week intervals) with boosters at 15 months inthe United States and at 4 years (United King-dom and United States). A further dose is rec-ommended in both the United States andUnited Kingdom within 5–10 years (table 2).Serum antitoxin concentrations above0.01U/ml are considered protective, althoughthere have been patients reported with protec-tive serum antibody concentrations.90–92 A pro-tective antibody concentration is attained afterthe second dose, but a third dose ensureslonger lasting immunity. To maintain adequateconcentrations of protection additional boosterdoses should be administered every 10 years.

Reactions to the tetanus toxoid are estimatedto be 1 in 50 000 injections, although most arenot severe; local tenderness, oedema, flu-likeillness, and low grade fever are the most oftenencountered. Severe reactions such asGuillian-Barré syndrome and acute relapsingpolyneuropathy are rare.93 94

In recent years there have been reports fromAustralia and the United States of tetanusoccurring in patients over the age of 50.95 96 Ina survey from the United States 59% of womenand 27% of men from an urban geriatric carecentre did not have adequate antitetanustitres.97 For every child in the United Stateswho dies of a vaccine preventable disease,about 400 adults die of such a disease.98 Thereis a strong argument for the introduction of avaccination strategy for the immunisation of alladults at the age of 50.

Neonatal tetanus can be prevented byimmunisation of women during pregnancy.Two or three doses of absorbed toxin should begiven with the last dose at least 1 month beforedelivery. Immunity is passively transferred tothe fetus and protective antibodies will persistlong enough to protect the baby. There is noevidence of congenital anomalies associatedwith tetanus toxin administered duringpregnancy.99

The influence of HIV infection on the trans-placental transfer of tetanus specific maternalIgG is of critical importance. Polyclonal hyper-immunoglobulinaemia is common in HIV andmay limit the transfer of protective maternalantibodies, as may HIV infection itself. Theantitetanus antibody concentrations werelower in babies born to 46 HIV infectedwomen than in a control HIV negative group,although still above 0.01 IU/ml.100 About 10%of babies born to mothers with a placentaheavily infected with Plasmodium falciparum myfail to acquire protective concentrations oftetanus antibody despite adequate maternalconcentrations.101 The antibody response totetanus vaccination is reduced in HIV infectedadult people with a CD4+ lymphocytecount <300×106/l.102 People infected with HIV

who completed their vaccination course beforeacquisition of HIV should maintain adequateprotection against tetanus.

Research on tetanus vaccines has concen-trated on a single dose vaccine, using technol-ogy such as microencapsulation.103 This wouldbe of most use in those countries where a threedose regime results in management diYculties.Strategies involving expression of the immuno-dominant HC domain in attenuated strains ofSalmonella followed by oral immunisation havebeen successful in animals, and may form thebasis of future multivalent oral vaccines.104

ConclusionThe World Health Organisation resolved toeliminate neonatal tetanus by 1995. Threeyears after the deadline the infection still killsover 400 000 babies a year. A safe eVectivevaccine has been available for most of this cen-tury. If any one disease epitomises the health-care disparity between the developed anddeveloping world, and the difficulties inovercoming that inequality, then tetanus is thatdisease. It is entirely preventable world wide.The priorities must be in prevention; universalvaccination, and the development of simplerimmunisation schedules with longer protec-tion. However, for the foreseeable futurehospitals in many parts of the developing worldwill continue to see many patients with tetanus.Further work on pragmatic solutions applica-ble in these countries is needed on how toreduce the high mortality. A better understand-ing of C tetani, the toxin, its eVects on the cen-tral and autonomic nervous system, andcardiac and respiratory function is needed.There is a tendency to accept a high mortalityfrom tetanus, Udwadia et al have shown inIndia that it is possible to substantially reducethe mortality even in the absence of fully-fledged intensive care units.107

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NEUROLOGICAL STAMP

Antonio Grossich (1849-1926)

Grossich studied medicine in Vienna, graduat-ing in 1875. He went to Fiume and becameChief of the Surgery Division at the City Hos-pital. Grossich was among the first to use steri-lisation of the operative field and in 1908 intro-duced tincture of iodine for rapid sterilisationof the human skin.

Fiume, formerly a port of Hungary wasclaimed by Yugoslavia and Italy after the firstworld war. Yugoslavia recognised Italy’s claimand the city was annexed in January 1924.Fiume was named Rijeka after the secondworld war. It is now a port city.

Grossich is known more as a patriot andhumanitarian than a surgeon. He was hon-oured philatelically by Fiume in 1919 on asemi-postal stamp (Stanley Gibbons 122, ScottB16).

L F HAAS

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