416
TETANUS: A DIAGNOSTIC CHALLENGE IN THE WESTERN WORLD
Original Article
TETANUS: A DIAGNOSTIC CHALLENGE IN THE WESTERN WORLD Van Driessche A1, Janssens B2, Coppens Y3, Bachmann C3, Donck J4 1
Department of Internal Medicine, UZ Gent, 9000 Ghent, Belgium, 2Intensive Care Unit, AZ Sint Lucas, 9000 Ghent, Belgium, 3Department of Geriatric Medicine, AZ Sint Lucas, 9000 Ghent, Belgium, 4Department of Nephrology, AZ Sint Lucas, 9000 Ghent, Belgium. Correspondence and offprint requests to: Annelien Van Driessche, E-mail: annelien.vandriessche@ ugent.be
ABSTRACT Tetanus is a very serious neuromuscular disease caused by a powerful exotoxin, tetanospasmin, from the Clostridium tetani bacillus. Its incidence in the developed world has diminished considerably since the introduction of primary vaccination. Tetanus is diagnosed clinically, through recognition of the characteristically inducible muscle spasms. Three clinical forms described in adults are generalised, localised and cephalic tetanus. Management of tetanus aims at removing the source of tetanospasmin, neutralising circulating toxin, and providing adequate supportive care for muscle spasms, respiration and autonomic instability. Tetanus is a forgotten disease in developed countries since many practicing primary care physicians have not seen a single case in their career. We present a case of tetanus and review briefly the pathogenesis, clinical features and therapy in order to educate the internist in recognising and adequately treating this disease. Key words: Tetanus, clostridium tetani, trismus, opisthotonus, neurotoxin.
INTRODUCTION Tetanus is a neuromuscular disorder caused by an anaerobic spore-forming bacterium, clostridium tetani, which is found in soil and in human and animal faeces. Although C. tetani is located everywhere, the disease is encountered mainly in underdeveloped and overcrowded regions. In developed countries, primary immunisation programmes have drastically reduced the incidence of tetanus. Tetanus is now such a rare disease that few Western clinicians have ever
Acta Clinica Belgica, 2013; 68-6
observed it. Yet, cases of this potentially life- threatening disease are still seen at times in primary health care. The prognosis of tetanus is favourable if it is diagnosed and treated promptly. Measures should be taken to increase awareness of this potentially lethal and disabling disease. The objectives of this article are: 1) to present a case report of tetanus in a primary health care setting; 2) to discuss the epidemiology of tetanus in Belgium and Europe; and 3) to review briefly the pathogenesis, clinical features and management of tetanus in order to educate the internist.
CASE REPORT A 65-year-old woman presented to our emergency department with vague complaints of general malaise, pain and motor weakness. Her medical history consisted of diminished renal function due to polycystic kidney disease, Menière’s disease and hypothyroidism. Since one day she experienced stiffness and diminished motor control in the left leg, leading to a fall after which she had difficulties to stand up, although the lady was in a good physical condition up tillthen. She considered herself weakened because of reduced food intake over the last few days, due to oropharyngeal problems. The patient described difficulties in mastication and swallowing, a painful sensation in the jaw and throat, and a feeling of “tight dentures”. Furthermore she complained of pain in the right flank after her recent fall, where indeed a fracture of the third rib was seen on X-ray. On clinical examination, we saw a patient in relatively good physical condition but rather neglected appearance. She had superficial wounds on her left lower leg, which were not cleaned properly. On routine neurologic examination there were no manifest abnormalities, except for the fact that the patient was unable to open her mouth well. Inspection of the mouth and throat was therefore not possible.
doi: 10.2143/ACB.3336
TETANUS: A DIAGNOSTIC CHALLENGE IN THE WESTERN WORLD
Laboratory investigations on admission revealed only stable chronic renal insufficiency with serum creatinine of 141.4 µmol/L (1.6 mg/dl). C-reactive protein was not elevated. In spite of her relatively young age and good general condition, the patient insisted in being hospitalised, and she was admitted to the geriatric department for observation. In the following days, the pain and motor disturbances in her left leg increased, as did the painful masseter muscle spasms. There was an extension of the tonic muscle contractions to the neck and subsequently to the whole body, eventually evolving to a typical opisthotonus triggered by the slightest stimulation. Based upon these typical clinical features, the patient was finally diagnosed with tetanus. Port of entry for the tetanus infection appeared to be the soiled injuries on her left leg, caused by scratches and bites from a chicken twelve days before admission. She had not received tetanus immunisation for years and it was not clear whether primary immunisation had been completed. Five days after her admission, the patient was transferred to the intensive care unit, and tetanus immunoglobulins were administered, together with active immunisation with tetanus anatoxin. Diazepam and propofol were used to control spasms and rigidity. She proceeded to develop respiratory difficulties requiring mechanical ventilation for several days. Adequate analgesia was provided first with morphine and later with fentanyl during mechanical ventilation. Empirical antibiotherapy was started with amoxicillin, followed by piperacillin/tazobactam for a Staphylococcus aureus ventilator-associated pneumonia. Autonomic dysfunction presented mainly with tachycardia and hypertension, and was treated with beta blockade. Nutritional support was given first enterally and afterwards parenterally. During the third week she started to improve clinically, and after almost three weeks in the ICU, the patient was transferred back to the regular ward for further recovery and revalidation.
DISCUSSION Epidemiology
The true incidence of tetanus is not known, but is estimated to be around one million cases per year worldwide, the majority of which occur in developing countries. In industrialised countries the epidemiology has changed thoroughly owing to universal immunisation programmes, and the disorder is nowadays only rarely seen. In Belgium, standard tetanus vaccination of infants started in 1959 (with a catch-up schedule for all children up to 15 years old). Just before the implementation of this generalised immunisation, the average number of tetanus cases in Belgium was about 68 per year (340 cases from 1954 to 1959), while afterwards the incidence rapidly declined to
34 cases annually (273 cases from 1960 to 1968). Subsequently a further decrease was seen in the number of cases from 3 to 4 yearly in the eighties and even lower in the nineties (from 1994 to 1997 only 7 cases of tetanus were reported in Flanders). In general, thanks to good vaccination strategies, the number of tetanus cases was reduced in Belgium from 1/100.000 residents in 1920 to 0.03/100.000 residents nowadays (FOD Volksgezondheid, Hoge Gezondheidsraad, Werkgroep Vaccinatie. Personal communication). Similarly, there is an obvious trend towards tetanus incidence reduction in Europe, thanks to immunisation campaigns and improvement in childbirth and neonatal care. At the beginning of the nineteenth century, more than 5000 patients died from this disease each year, but the number decreased to 1000 during 1971-1980. Gasparini et al. showed a significant decrease in the number of tetanus cases in Europe during 1975-1994 (1). Although the incidence of tetanus has strikingly reduced, there are still a few cases reported every year in Belgium and other European countries (Table 1) (2). The majority of cases concern elderly, in particular women. The elderly population has the highest risk for tetanus since they may not have had tetanus immunisation or regular booster injections. The female predisposition can be explained by vaccination of men during military service, and by the fact that men are more likely to receive booster vaccines due to gender-specific differences in professional and leisure activities. Other risk factors for tetanus disease are intravenous drug use and diabetes mellitus. Although the importance of tetanus vaccination has been largely established, the vaccination status in Belgium is still sub-optimal. A large-scale population survey in 1997 concluded that 32% of the Belgian population aged 15 years and older had not been vaccinated for tetanus in the last ten years. Women were less vaccinated (59%) than men (76%). The percentage of the population that was not vaccinated increased with age: from only 10% between 15 and 24 years old, up to 70% for people aged 75 years and older (3). Under 15 years of age, on the other hand, a satisfactory vaccination status is demonstrated. In 2012, a vaccination level of 93% has been shown in infants from 18 to 24 months (which means they received full immunisation with 4 vaccines) and of 90.8% in 14-year-old adolescents (receipt of initial immunisation and the booster around age 6) (4). Serological data about tetanus coverage in Belgium are scarce. Theeten et al. showed immunity to tetanus in 87.2% of adults > 40 years. The proportion of patients with a seroprotective anti-tetanus level (> 0.15 IU/ml) decreased slightly with age to a minimum of 79.6% in the 60-65 years age group. The results of this sero-survey in Belgium indicate suboptimal protection against tetanus in older adults. Efforts should focus on enhancing the implementation of regular tetanus vaccine boosters, especially in this age group (5).
Table 1: Number of tetanus cases reported in Belgium and in Europe from 1997 to 2006 (2) 1997 Belgium Europe
1998
1999
2000
2001
2002
2003
2004
2005
2006
1
0
1
1
3
1
1
2
3
1
309
290
288
263
220
188
219
177
147
170
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Pathogenesis
Clostridium tetani is a Gram-positive, obligate anaerobic bacillus, which forms spores that are extremely stable, and widely found in soil and in animal faeces. Tetanus can occur when spores of the bacterium are inoculated into a wound. The spores germinate and the resultant bacteria multiply and produce a potent neurotoxin, known as tetanospasmin, responsible for the clinical features of the disease (6). A second toxin, tetanolysin, is thought to contribute to an anaerobic environment by damaging viable tissue. Tetanospasmin enters peripheral nerves, and after retrograde axonal transport to the central nervous system, blocks inhibitory nerve synapses in the spinal cord and brainstem. This results in sustained excitatory discharge causing the characteristic motor spasms and autonomic dysfunction. The binding of the neurotoxin to nerve tissue is irreversible and recovery occurs only with the growth of new nerve terminals, which explains the typical 2-3 week period before clinical improvement begins (7).
Clinical features
Tetanus typically follows deep penetrating wounds where anaerobic bacterial growth is facilitated. However, even minor trauma can lead to disease, and in up to 30% of patients no portal of entry is apparent (8). The incubation period for tetanus varies from a few days to several weeks, with most cases occurring within 7 to 10 days of the initial injury (9; 6). The incubation period depends on specific conditions at the site of spore deposition and on the localisation of the injury, since the lag period becomes longer with increasing distance of the wound from the spinal cord. The clinical picture is dominated by muscle spasms, rigidity, and autonomic disturbances. Muscle stiffness, sore throat, dysphagia and difficulty opening the mouth are usually the earliest features. Masseter spasm causes trismus (lockjaw), and extension to the facial muscles leads to a characteristic facial expression known as “risus sardonicus”. Respiratory failure is the most common direct cause of death from tetanus, and is the result of diaphragmatic paralysis and laryngeal obstruction due to muscle spasms. Tonic spasms of muscles of the neck, back, trunk, limbs and abdomen may be associated with rigid arching of the back in a characteristic opisthotonus. These extremely painful episodic spasms can occur spontaneously or may be triggered by touch, visual, auditory or emotional stimuli. Autonomic dysfunction produces tachycardia, labile hypertension, sweating and cardiac arrhythmias. The muscular contractions of tetanus can be either localised or generalised. Generalised tetanus is the most common form, with the head and neck being usually affected first, followed by a caudal spread of spasm. Localised tetanus is a milder form of the disease, and occurs if the rigidity and pain remain close to the site of the wound. The rigidity may linger for weeks to months and often resolves without sequelae. Secondary generalisation may occur, with localised tetanus in fact being the first symptom of the generalised form. Cephalic tetanus is an uncommon variant of localised tetanus that involves the cranial nerves. With its predilection for the 7th cranial nerve, it commonly mimics Bell’s Palsy. Head trauma and otitis media are cited aetiologies for cephalic tetanus (6). Apart from sedation associated with use of drugs in tetanus, consciousness is usually preserved in patients with
Acta Clinica Belgica, 2013; 68-6
uncomplicated tetanus, so that spasms are experienced with severe pain. The average duration of the illness is six weeks, comprising a two-week progression period and another four weeks for recovery. Most adults start to recover once the muscle spasms have subsided. In the majority of cases recovery is complete (10).
Differential diagnosis
The diagnosis of tetanus must be made on clinical findings outlined above, as there are no laboratory tests that can diagnose or rule-out tetanus. A “protective” serum antitoxin antibody level makes the diagnosis of tetanus unlikely but not impossible; moreover, antitoxin antibody levels are not likely to be available at the time when management decisions must be made. The differential diagnosis may be diverse (Table 2). Intense muscle rigidity and trismus can be mistaken for acute dystonic reactions. Trismus may also be caused by oro-facial infections or abscesses. Strychnine poisoning, due to accidental or intentional ingestion of rat poison, can closely resemble generalised tetanus. Cephalic tetanus may be difficult to differentiate from other causes of cranial nerve palsies such as Bell’s Palsy, CNS tumor or stroke. Hypocalcaemia causing tetany should be excluded with laboratory testing. Other entities that cause diffuse muscle spasms, such as seizures, toxidromes and encephalopathies, are accompanied by changes in mental status. Myopathies or neuropathies tend to cause weakness rather than spasms and rigidity. Stiff-person syndrome is a rare neurologic disorder characterized by severe muscle rigidity, but in absence of trismus or facial spasms and rapidly responding to diazepam (7).
Prevention
Tetanus prophylaxis is the cornerstone of disease prevention. In Belgium, all children are offered a full course of tetanus immunisation consisting of six doses of vaccines: three doses in infancy, followed by boosters at age 15 months, 5 through 7 years, and 14 through 16 years. The Superior Health Council recommends a booster every ten years after receiving the full six doses of vaccine (11, 12).
Table 2: Differential diagnoses of tetanus (7) Cephalic tetanus
–– Bell’s Palsy –– CNS tumor –– Stroke
Trismus
–– Orofacial infection or abscess –– Dystonic reaction
Diffuse muscle spasms
–– Seizures –– Toxidromes –– Encephalopathies –– Stiff-person syndrome
Local muscle dysfunction
–– Myopathies –– Neuropathies –– (Drug induced) dystonias
Autonomic instability (+/– muscular rigidity)
–– Malignant neuroleptic syndrome
Generalized tetanus
–– Strychnine poisoning –– Tetany secondary to hypocalcemia
Neonatal tetanus
–– Infectious, toxic and metabolic aetiologies
TETANUS: A DIAGNOSTIC CHALLENGE IN THE WESTERN WORLD
If a patient presents with an injury, a tetanus toxoid vaccine should be given if the last dose was administered more than 10 years ago (or 5 years in the case of severe injury). The immunisation schedule should be completed in patients who did not receive all doses of the basic schedule. If the wound is considered to be high risk, human tetanus immunoglobulin (HTIG) may be needed to ensure instant protection, the schedule for which is summarised in table 3 (source: Superior Health Council Belgium). The standard prophylactic HTIG dosage is 250 IU, although the dose may be increased to 500 IU in case of deep or contaminated wounds. However, given the variability in tetanus seroprotection rates, it is difficult to identify which patients require either a booster toxoid dose or prophylactic HTIG. Questioning patients about their immune status is highly imprecise, and most patients seen in the emergency department do not carry certificates. This may result in over-immunisation of patients who have previously received full immunisation or under-immunisation of patients who incorrectly claim to be immunised. Laboratory tests assessing serum antitoxoid levels are too technically demanding and time-consuming to be useful (13). The Tétanos Quick Stick (TQS; Gamma, Belgium) is an immunochromatographic test for bedside semiquantitative evaluation of anti-tetanus antibodies in human blood. The patient’s blood (e.g. from fingerprick), serum or plasma is added to the sample well of the dipstick. If antitetanus antibodies are present in the sample, a pink line is seen in the test (T) zone. A pink line formed in the control (C) zone indicates that the test has been carried out correctly. The result is available within 10 minutes. The detection threshold is claimed to be 0.1 IU/mL for serum and 0.2 IU/mL for whole blood. The TQS is a reliable and effective tool for the detection of a protective antibody level in patients presenting to the emergency department (14, 15). Moreover, it has shown to be costeffective in Belgium for patients who are believed to be unprotected by their vaccination history (unknown vaccination status, incomplete vaccination programme, or lack of booster in the last 10 years) (14, 16).
Management of tetanus
When tetanus is suspected, any wound must be cleaned and debrided if necessary, to eradicate spores and necrotic tissue. Although antibiotics for Clostridium tetani probably play a relatively minor part in the specific treatment of the disease, they are usually recommended. Metronidazole may be the preferred antibiotic, although penicillin is a safe and effective alternative (8).
Passive immunisation with HTIG is considered to be standard treatment, as it shortens the course and may reduce the severity of the illness (6). It neutralises unbound tetanospasmin, but cannot inactivate toxin once it has entered the neurons. Its half-life is 25 days, so only a single dose is necessary. The optimal dose of HTIG is not well defined. In a 1976 retrospective study on the effect of different doses, 500 IU was found to be as effective as the 3000-10000 IU doses that were commonly used. The smaller dose has the advantage of requiring fewer injections (HTIG is supplied in 250 IU doses), which is important because injections are powerful stimuli for spasms (7, 17). The World Health Organisation (WHO) recommends administration of 500 IU intramuscularly or intravenously. Active immunisation with tetanus toxoid is important to provide longer term humoral and cellular immunity. As the amount of tetanospasmin produced in clinical tetanus is small and partially sequestered in neurons, an immune response does not occur and immunity following tetanus is incomplete. Consequently, it is important that all patients receive a total immunisation series (6). Treatment of tetanus muscle spasms and rigidity is one of the most important aspects in the management of tetanus disease. As external stimuli provoke muscle spasms and may worsen the autonomic disturbances they should be kept as low as possible. Furthermore all patients should receive adequate sedation. Diazepam is most commonly used for its anticonvulsant, muscle relaxant, sedative and anxiety reducing effects. Midazolam, morphine and propofol also have useful sedative and muscle relaxant properties. If muscle spasms persist despite adequate sedation, powerful muscle relaxants may be required. Agents that have been administered include dantrolene, baclofen, and neuromuscular blocking agents such as pancuronium and vecuronium (10). If there is any respiratory impairment, or when paralytics are used, assisted ventilation is required. Artificial respiration can be applied through orotracheal intubation or tracheostomy (6; 7). Autonomic functions should be monitored and any specific complication treated as it arises (6). Sedation, which is useful for controlling spasms and rigidity, is also the first step in reducing autonomic instability (8). Both alpha- and betablockers have been administered, but labetalol is preferred because of its dual alpha- and beta-blocking properties. Morphine and fentanyl centrally decrease sympathetic outflow; and magnesium sulphate blunts catecholamine release from nerves and reduces receptor responsiveness to released catecholamines (7). Energy demands in tetanus may be very high due to muscular contractions, excessive sweating, and sepsis, so early
Table 3: Tetanus prophylaxis in case of injuries (source: Superior Health Council Belgium) Vaccination status
Superficial and clean wound
Tetanus-prone wound
No or uncertain basic schedule
Full basic schedule
Full basic schedule + HTIG
Incomplete basic schedule
Complete the immunisation schedule
Complete the immunisation schedule + HTIG
Full basic schedule –– Last vaccine 5 years and 10 years and 20 years
– – 1 dose of vaccine 2 doses of vaccine with 6 months interval
– 1 dose of vaccine 1 dose of vaccine + HTIG 2 doses of vaccine with 6 months interval + HTIG
HTIG: Human Tetanus Immunoglobulin.
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nutritional support is essential. Enteral feeding has advantages over parenteral feeding, and percutaneous endoscopic gastrostomy may be established. Finally, physical therapy is important as soon as spasms have ceased, to help patients recover from prolonged druginduced paralysis and immobilization.
REFERENCES 1. Gasparini R, Montomoli E, Massafra S, et al. Tetanus epidemiology in Europe and in Italy: a review. J Prev Med Hyg 1999; 77-82. 2. Joint Questionnaire DG SANCO / Eurostat until 2005 and ECDC (the European Centre for Disease Prevention and Control) from 2006 onwards. Indicator No. 18-Tet (SL88) updated by SANCO.C.2 in March 2009. 3. Demarest S, Leurquin P, Tafforeau J, Tellier V, Van der Heyden J, Van Oyen H. De gezondheid van de bevolking in België. Gezondheidsenquête door middel van Interview, België, 1997. Afdeling Epidemiologie, 1998; Brussel. Wetenschappelijk Instituut Volksgezondheid. 4. Van Damme P, Theeten H, Brackman T, et al. Studie van de vaccinatiegraad bij jonge kinderen en adolescenten in Vlaanderen in 2012. Studie in opdracht van de Vlaamse Overheid, Vlaams Agentschap Zorg en Gezondheid, Afdeling Toezicht Volksgezondheid, Team infectieziekten. Januari 2013. 5. Theeten H, Hutse V, Hens N, et al. Are we hitting immunity targets? The 2006 age-specific seroprevalence of measles, mumps, rubella, diphtheria and tetanus in Belgium. Epidemiol Infect 2011; 139(4): 494-504.
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6. Goonetilleke A, Harris JB. Clostridial neurotoxins. J Nurol Neurosurg Psychiatry 2004; 75 Suppl 3: iii35-39. 7. Hsu SS, Groleau G. Tetanus in the emergency department: a current review. J Emerg Med 2001; 20(4): 357-365. 8. Farrar JJ, Yen LM, Cook T, et al. Tetanus. J neurol Neurosurg Psychiatry 2000; 69(3): 292-301. 9. Finch RG, Moss P, Jeffries DJ, Anderson J. Toxin-mediated infections. In: Clinical medicine. United Kingdom: Kumar P, Clark M. 2002: 76-77. 10. Okoromah CN, Lesi FE. Diazepam for treating tetanus. Cochrane Database Syst Rev 2004; (1): CD003954. 11. Vaccinatie tegen difterie, tetanus en kinkhoest: vaccinatie van kinderen en adolescenten. Herziening 2013. Hoge Gezondheidsraad België. 12. Vaccinatie tegen tetanus: vaccinatie van volwassenen. Herziening 2013. Hoge gezondheidsraad België. 13. Cooke MW. Are current UK tetanus prophylaxis procedures for wound management optimal? Emerg Med J 2009; 26(12): 845-848. 14. Stubbe M, Swinnen R, Crusiaux A, Mascart F, Lheureux PE. Seroprotection against tetanus in patients attending an emergency department in Belgium and evaluation of a bedside immunotest. Eur J Emerg Med 2007; 14(1): 14-24. 15. Elkharrat D, Sanson-Le-Pors MJ, Arrouy L, Beauchet A, Benhamou F. Evaluation of a bedside immunotest to predict individual anti-tetanus seroprotection: a prospective concordance study of 1018 adults in an emergency department. Emerg Med J 2010; 27(1): 36-42. 16. Stubbe M, Mortelmans LJ, Desruelles D, et al. Improving tetanus prophylaxis in the emergency department: a prospective, double-blind cost-effectiveness study. Emerg Med J 2007; 24(9): 648-653. 17. Blake PA, Feldman RA, Buchanan TM, Brooks GF, Bennett JV. Serologic therapy of tetanus in the United States, 1965-1971. JAMA 1976; 235(1): 42-44.
TETANUS: A DIAGNOSTIC CHALLENGE IN THE WESTERN WORLD
Original Article
TETANUS: A DIAGNOSTIC CHALLENGE IN THE WESTERN WORLD Van Driessche A1, Janssens B2, Coppens Y3, Bachmann C3, Donck J4 1
Department of Internal Medicine, UZ Gent, 9000 Ghent, Belgium, 2Intensive Care Unit, AZ Sint Lucas, 9000 Ghent, Belgium, 3Department of Geriatric Medicine, AZ Sint Lucas, 9000 Ghent, Belgium, 4Department of Nephrology, AZ Sint Lucas, 9000 Ghent, Belgium. Correspondence and offprint requests to: Annelien Van Driessche, E-mail: annelien.vandriessche@ ugent.be
ABSTRACT Tetanus is a very serious neuromuscular disease caused by a powerful exotoxin, tetanospasmin, from the Clostridium tetani bacillus. Its incidence in the developed world has diminished considerably since the introduction of primary vaccination. Tetanus is diagnosed clinically, through recognition of the characteristically inducible muscle spasms. Three clinical forms described in adults are generalised, localised and cephalic tetanus. Management of tetanus aims at removing the source of tetanospasmin, neutralising circulating toxin, and providing adequate supportive care for muscle spasms, respiration and autonomic instability. Tetanus is a forgotten disease in developed countries since many practicing primary care physicians have not seen a single case in their career. We present a case of tetanus and review briefly the pathogenesis, clinical features and therapy in order to educate the internist in recognising and adequately treating this disease. Key words: Tetanus, clostridium tetani, trismus, opisthotonus, neurotoxin.
INTRODUCTION Tetanus is a neuromuscular disorder caused by an anaerobic spore-forming bacterium, clostridium tetani, which is found in soil and in human and animal faeces. Although C. tetani is located everywhere, the disease is encountered mainly in underdeveloped and overcrowded regions. In developed countries, primary immunisation programmes have drastically reduced the incidence of tetanus. Tetanus is now such a rare disease that few Western clinicians have ever
Acta Clinica Belgica, 2013; 68-6
observed it. Yet, cases of this potentially life- threatening disease are still seen at times in primary health care. The prognosis of tetanus is favourable if it is diagnosed and treated promptly. Measures should be taken to increase awareness of this potentially lethal and disabling disease. The objectives of this article are: 1) to present a case report of tetanus in a primary health care setting; 2) to discuss the epidemiology of tetanus in Belgium and Europe; and 3) to review briefly the pathogenesis, clinical features and management of tetanus in order to educate the internist.
CASE REPORT A 65-year-old woman presented to our emergency department with vague complaints of general malaise, pain and motor weakness. Her medical history consisted of diminished renal function due to polycystic kidney disease, Menière’s disease and hypothyroidism. Since one day she experienced stiffness and diminished motor control in the left leg, leading to a fall after which she had difficulties to stand up, although the lady was in a good physical condition up tillthen. She considered herself weakened because of reduced food intake over the last few days, due to oropharyngeal problems. The patient described difficulties in mastication and swallowing, a painful sensation in the jaw and throat, and a feeling of “tight dentures”. Furthermore she complained of pain in the right flank after her recent fall, where indeed a fracture of the third rib was seen on X-ray. On clinical examination, we saw a patient in relatively good physical condition but rather neglected appearance. She had superficial wounds on her left lower leg, which were not cleaned properly. On routine neurologic examination there were no manifest abnormalities, except for the fact that the patient was unable to open her mouth well. Inspection of the mouth and throat was therefore not possible.
doi: 10.2143/ACB.3336
TETANUS: A DIAGNOSTIC CHALLENGE IN THE WESTERN WORLD
Laboratory investigations on admission revealed only stable chronic renal insufficiency with serum creatinine of 141.4 µmol/L (1.6 mg/dl). C-reactive protein was not elevated. In spite of her relatively young age and good general condition, the patient insisted in being hospitalised, and she was admitted to the geriatric department for observation. In the following days, the pain and motor disturbances in her left leg increased, as did the painful masseter muscle spasms. There was an extension of the tonic muscle contractions to the neck and subsequently to the whole body, eventually evolving to a typical opisthotonus triggered by the slightest stimulation. Based upon these typical clinical features, the patient was finally diagnosed with tetanus. Port of entry for the tetanus infection appeared to be the soiled injuries on her left leg, caused by scratches and bites from a chicken twelve days before admission. She had not received tetanus immunisation for years and it was not clear whether primary immunisation had been completed. Five days after her admission, the patient was transferred to the intensive care unit, and tetanus immunoglobulins were administered, together with active immunisation with tetanus anatoxin. Diazepam and propofol were used to control spasms and rigidity. She proceeded to develop respiratory difficulties requiring mechanical ventilation for several days. Adequate analgesia was provided first with morphine and later with fentanyl during mechanical ventilation. Empirical antibiotherapy was started with amoxicillin, followed by piperacillin/tazobactam for a Staphylococcus aureus ventilator-associated pneumonia. Autonomic dysfunction presented mainly with tachycardia and hypertension, and was treated with beta blockade. Nutritional support was given first enterally and afterwards parenterally. During the third week she started to improve clinically, and after almost three weeks in the ICU, the patient was transferred back to the regular ward for further recovery and revalidation.
DISCUSSION Epidemiology
The true incidence of tetanus is not known, but is estimated to be around one million cases per year worldwide, the majority of which occur in developing countries. In industrialised countries the epidemiology has changed thoroughly owing to universal immunisation programmes, and the disorder is nowadays only rarely seen. In Belgium, standard tetanus vaccination of infants started in 1959 (with a catch-up schedule for all children up to 15 years old). Just before the implementation of this generalised immunisation, the average number of tetanus cases in Belgium was about 68 per year (340 cases from 1954 to 1959), while afterwards the incidence rapidly declined to
34 cases annually (273 cases from 1960 to 1968). Subsequently a further decrease was seen in the number of cases from 3 to 4 yearly in the eighties and even lower in the nineties (from 1994 to 1997 only 7 cases of tetanus were reported in Flanders). In general, thanks to good vaccination strategies, the number of tetanus cases was reduced in Belgium from 1/100.000 residents in 1920 to 0.03/100.000 residents nowadays (FOD Volksgezondheid, Hoge Gezondheidsraad, Werkgroep Vaccinatie. Personal communication). Similarly, there is an obvious trend towards tetanus incidence reduction in Europe, thanks to immunisation campaigns and improvement in childbirth and neonatal care. At the beginning of the nineteenth century, more than 5000 patients died from this disease each year, but the number decreased to 1000 during 1971-1980. Gasparini et al. showed a significant decrease in the number of tetanus cases in Europe during 1975-1994 (1). Although the incidence of tetanus has strikingly reduced, there are still a few cases reported every year in Belgium and other European countries (Table 1) (2). The majority of cases concern elderly, in particular women. The elderly population has the highest risk for tetanus since they may not have had tetanus immunisation or regular booster injections. The female predisposition can be explained by vaccination of men during military service, and by the fact that men are more likely to receive booster vaccines due to gender-specific differences in professional and leisure activities. Other risk factors for tetanus disease are intravenous drug use and diabetes mellitus. Although the importance of tetanus vaccination has been largely established, the vaccination status in Belgium is still sub-optimal. A large-scale population survey in 1997 concluded that 32% of the Belgian population aged 15 years and older had not been vaccinated for tetanus in the last ten years. Women were less vaccinated (59%) than men (76%). The percentage of the population that was not vaccinated increased with age: from only 10% between 15 and 24 years old, up to 70% for people aged 75 years and older (3). Under 15 years of age, on the other hand, a satisfactory vaccination status is demonstrated. In 2012, a vaccination level of 93% has been shown in infants from 18 to 24 months (which means they received full immunisation with 4 vaccines) and of 90.8% in 14-year-old adolescents (receipt of initial immunisation and the booster around age 6) (4). Serological data about tetanus coverage in Belgium are scarce. Theeten et al. showed immunity to tetanus in 87.2% of adults > 40 years. The proportion of patients with a seroprotective anti-tetanus level (> 0.15 IU/ml) decreased slightly with age to a minimum of 79.6% in the 60-65 years age group. The results of this sero-survey in Belgium indicate suboptimal protection against tetanus in older adults. Efforts should focus on enhancing the implementation of regular tetanus vaccine boosters, especially in this age group (5).
Table 1: Number of tetanus cases reported in Belgium and in Europe from 1997 to 2006 (2) 1997 Belgium Europe
1998
1999
2000
2001
2002
2003
2004
2005
2006
1
0
1
1
3
1
1
2
3
1
309
290
288
263
220
188
219
177
147
170
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418
TETANUS: A DIAGNOSTIC CHALLENGE IN THE WESTERN WORLD
Pathogenesis
Clostridium tetani is a Gram-positive, obligate anaerobic bacillus, which forms spores that are extremely stable, and widely found in soil and in animal faeces. Tetanus can occur when spores of the bacterium are inoculated into a wound. The spores germinate and the resultant bacteria multiply and produce a potent neurotoxin, known as tetanospasmin, responsible for the clinical features of the disease (6). A second toxin, tetanolysin, is thought to contribute to an anaerobic environment by damaging viable tissue. Tetanospasmin enters peripheral nerves, and after retrograde axonal transport to the central nervous system, blocks inhibitory nerve synapses in the spinal cord and brainstem. This results in sustained excitatory discharge causing the characteristic motor spasms and autonomic dysfunction. The binding of the neurotoxin to nerve tissue is irreversible and recovery occurs only with the growth of new nerve terminals, which explains the typical 2-3 week period before clinical improvement begins (7).
Clinical features
Tetanus typically follows deep penetrating wounds where anaerobic bacterial growth is facilitated. However, even minor trauma can lead to disease, and in up to 30% of patients no portal of entry is apparent (8). The incubation period for tetanus varies from a few days to several weeks, with most cases occurring within 7 to 10 days of the initial injury (9; 6). The incubation period depends on specific conditions at the site of spore deposition and on the localisation of the injury, since the lag period becomes longer with increasing distance of the wound from the spinal cord. The clinical picture is dominated by muscle spasms, rigidity, and autonomic disturbances. Muscle stiffness, sore throat, dysphagia and difficulty opening the mouth are usually the earliest features. Masseter spasm causes trismus (lockjaw), and extension to the facial muscles leads to a characteristic facial expression known as “risus sardonicus”. Respiratory failure is the most common direct cause of death from tetanus, and is the result of diaphragmatic paralysis and laryngeal obstruction due to muscle spasms. Tonic spasms of muscles of the neck, back, trunk, limbs and abdomen may be associated with rigid arching of the back in a characteristic opisthotonus. These extremely painful episodic spasms can occur spontaneously or may be triggered by touch, visual, auditory or emotional stimuli. Autonomic dysfunction produces tachycardia, labile hypertension, sweating and cardiac arrhythmias. The muscular contractions of tetanus can be either localised or generalised. Generalised tetanus is the most common form, with the head and neck being usually affected first, followed by a caudal spread of spasm. Localised tetanus is a milder form of the disease, and occurs if the rigidity and pain remain close to the site of the wound. The rigidity may linger for weeks to months and often resolves without sequelae. Secondary generalisation may occur, with localised tetanus in fact being the first symptom of the generalised form. Cephalic tetanus is an uncommon variant of localised tetanus that involves the cranial nerves. With its predilection for the 7th cranial nerve, it commonly mimics Bell’s Palsy. Head trauma and otitis media are cited aetiologies for cephalic tetanus (6). Apart from sedation associated with use of drugs in tetanus, consciousness is usually preserved in patients with
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uncomplicated tetanus, so that spasms are experienced with severe pain. The average duration of the illness is six weeks, comprising a two-week progression period and another four weeks for recovery. Most adults start to recover once the muscle spasms have subsided. In the majority of cases recovery is complete (10).
Differential diagnosis
The diagnosis of tetanus must be made on clinical findings outlined above, as there are no laboratory tests that can diagnose or rule-out tetanus. A “protective” serum antitoxin antibody level makes the diagnosis of tetanus unlikely but not impossible; moreover, antitoxin antibody levels are not likely to be available at the time when management decisions must be made. The differential diagnosis may be diverse (Table 2). Intense muscle rigidity and trismus can be mistaken for acute dystonic reactions. Trismus may also be caused by oro-facial infections or abscesses. Strychnine poisoning, due to accidental or intentional ingestion of rat poison, can closely resemble generalised tetanus. Cephalic tetanus may be difficult to differentiate from other causes of cranial nerve palsies such as Bell’s Palsy, CNS tumor or stroke. Hypocalcaemia causing tetany should be excluded with laboratory testing. Other entities that cause diffuse muscle spasms, such as seizures, toxidromes and encephalopathies, are accompanied by changes in mental status. Myopathies or neuropathies tend to cause weakness rather than spasms and rigidity. Stiff-person syndrome is a rare neurologic disorder characterized by severe muscle rigidity, but in absence of trismus or facial spasms and rapidly responding to diazepam (7).
Prevention
Tetanus prophylaxis is the cornerstone of disease prevention. In Belgium, all children are offered a full course of tetanus immunisation consisting of six doses of vaccines: three doses in infancy, followed by boosters at age 15 months, 5 through 7 years, and 14 through 16 years. The Superior Health Council recommends a booster every ten years after receiving the full six doses of vaccine (11, 12).
Table 2: Differential diagnoses of tetanus (7) Cephalic tetanus
–– Bell’s Palsy –– CNS tumor –– Stroke
Trismus
–– Orofacial infection or abscess –– Dystonic reaction
Diffuse muscle spasms
–– Seizures –– Toxidromes –– Encephalopathies –– Stiff-person syndrome
Local muscle dysfunction
–– Myopathies –– Neuropathies –– (Drug induced) dystonias
Autonomic instability (+/– muscular rigidity)
–– Malignant neuroleptic syndrome
Generalized tetanus
–– Strychnine poisoning –– Tetany secondary to hypocalcemia
Neonatal tetanus
–– Infectious, toxic and metabolic aetiologies
TETANUS: A DIAGNOSTIC CHALLENGE IN THE WESTERN WORLD
If a patient presents with an injury, a tetanus toxoid vaccine should be given if the last dose was administered more than 10 years ago (or 5 years in the case of severe injury). The immunisation schedule should be completed in patients who did not receive all doses of the basic schedule. If the wound is considered to be high risk, human tetanus immunoglobulin (HTIG) may be needed to ensure instant protection, the schedule for which is summarised in table 3 (source: Superior Health Council Belgium). The standard prophylactic HTIG dosage is 250 IU, although the dose may be increased to 500 IU in case of deep or contaminated wounds. However, given the variability in tetanus seroprotection rates, it is difficult to identify which patients require either a booster toxoid dose or prophylactic HTIG. Questioning patients about their immune status is highly imprecise, and most patients seen in the emergency department do not carry certificates. This may result in over-immunisation of patients who have previously received full immunisation or under-immunisation of patients who incorrectly claim to be immunised. Laboratory tests assessing serum antitoxoid levels are too technically demanding and time-consuming to be useful (13). The Tétanos Quick Stick (TQS; Gamma, Belgium) is an immunochromatographic test for bedside semiquantitative evaluation of anti-tetanus antibodies in human blood. The patient’s blood (e.g. from fingerprick), serum or plasma is added to the sample well of the dipstick. If antitetanus antibodies are present in the sample, a pink line is seen in the test (T) zone. A pink line formed in the control (C) zone indicates that the test has been carried out correctly. The result is available within 10 minutes. The detection threshold is claimed to be 0.1 IU/mL for serum and 0.2 IU/mL for whole blood. The TQS is a reliable and effective tool for the detection of a protective antibody level in patients presenting to the emergency department (14, 15). Moreover, it has shown to be costeffective in Belgium for patients who are believed to be unprotected by their vaccination history (unknown vaccination status, incomplete vaccination programme, or lack of booster in the last 10 years) (14, 16).
Management of tetanus
When tetanus is suspected, any wound must be cleaned and debrided if necessary, to eradicate spores and necrotic tissue. Although antibiotics for Clostridium tetani probably play a relatively minor part in the specific treatment of the disease, they are usually recommended. Metronidazole may be the preferred antibiotic, although penicillin is a safe and effective alternative (8).
Passive immunisation with HTIG is considered to be standard treatment, as it shortens the course and may reduce the severity of the illness (6). It neutralises unbound tetanospasmin, but cannot inactivate toxin once it has entered the neurons. Its half-life is 25 days, so only a single dose is necessary. The optimal dose of HTIG is not well defined. In a 1976 retrospective study on the effect of different doses, 500 IU was found to be as effective as the 3000-10000 IU doses that were commonly used. The smaller dose has the advantage of requiring fewer injections (HTIG is supplied in 250 IU doses), which is important because injections are powerful stimuli for spasms (7, 17). The World Health Organisation (WHO) recommends administration of 500 IU intramuscularly or intravenously. Active immunisation with tetanus toxoid is important to provide longer term humoral and cellular immunity. As the amount of tetanospasmin produced in clinical tetanus is small and partially sequestered in neurons, an immune response does not occur and immunity following tetanus is incomplete. Consequently, it is important that all patients receive a total immunisation series (6). Treatment of tetanus muscle spasms and rigidity is one of the most important aspects in the management of tetanus disease. As external stimuli provoke muscle spasms and may worsen the autonomic disturbances they should be kept as low as possible. Furthermore all patients should receive adequate sedation. Diazepam is most commonly used for its anticonvulsant, muscle relaxant, sedative and anxiety reducing effects. Midazolam, morphine and propofol also have useful sedative and muscle relaxant properties. If muscle spasms persist despite adequate sedation, powerful muscle relaxants may be required. Agents that have been administered include dantrolene, baclofen, and neuromuscular blocking agents such as pancuronium and vecuronium (10). If there is any respiratory impairment, or when paralytics are used, assisted ventilation is required. Artificial respiration can be applied through orotracheal intubation or tracheostomy (6; 7). Autonomic functions should be monitored and any specific complication treated as it arises (6). Sedation, which is useful for controlling spasms and rigidity, is also the first step in reducing autonomic instability (8). Both alpha- and betablockers have been administered, but labetalol is preferred because of its dual alpha- and beta-blocking properties. Morphine and fentanyl centrally decrease sympathetic outflow; and magnesium sulphate blunts catecholamine release from nerves and reduces receptor responsiveness to released catecholamines (7). Energy demands in tetanus may be very high due to muscular contractions, excessive sweating, and sepsis, so early
Table 3: Tetanus prophylaxis in case of injuries (source: Superior Health Council Belgium) Vaccination status
Superficial and clean wound
Tetanus-prone wound
No or uncertain basic schedule
Full basic schedule
Full basic schedule + HTIG
Incomplete basic schedule
Complete the immunisation schedule
Complete the immunisation schedule + HTIG
Full basic schedule –– Last vaccine 5 years and 10 years and 20 years
– – 1 dose of vaccine 2 doses of vaccine with 6 months interval
– 1 dose of vaccine 1 dose of vaccine + HTIG 2 doses of vaccine with 6 months interval + HTIG
HTIG: Human Tetanus Immunoglobulin.
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419
420
TETANUS: A DIAGNOSTIC CHALLENGE IN THE WESTERN WORLD
nutritional support is essential. Enteral feeding has advantages over parenteral feeding, and percutaneous endoscopic gastrostomy may be established. Finally, physical therapy is important as soon as spasms have ceased, to help patients recover from prolonged druginduced paralysis and immobilization.
REFERENCES 1. Gasparini R, Montomoli E, Massafra S, et al. Tetanus epidemiology in Europe and in Italy: a review. J Prev Med Hyg 1999; 77-82. 2. Joint Questionnaire DG SANCO / Eurostat until 2005 and ECDC (the European Centre for Disease Prevention and Control) from 2006 onwards. Indicator No. 18-Tet (SL88) updated by SANCO.C.2 in March 2009. 3. Demarest S, Leurquin P, Tafforeau J, Tellier V, Van der Heyden J, Van Oyen H. De gezondheid van de bevolking in België. Gezondheidsenquête door middel van Interview, België, 1997. Afdeling Epidemiologie, 1998; Brussel. Wetenschappelijk Instituut Volksgezondheid. 4. Van Damme P, Theeten H, Brackman T, et al. Studie van de vaccinatiegraad bij jonge kinderen en adolescenten in Vlaanderen in 2012. Studie in opdracht van de Vlaamse Overheid, Vlaams Agentschap Zorg en Gezondheid, Afdeling Toezicht Volksgezondheid, Team infectieziekten. Januari 2013. 5. Theeten H, Hutse V, Hens N, et al. Are we hitting immunity targets? The 2006 age-specific seroprevalence of measles, mumps, rubella, diphtheria and tetanus in Belgium. Epidemiol Infect 2011; 139(4): 494-504.
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6. Goonetilleke A, Harris JB. Clostridial neurotoxins. J Nurol Neurosurg Psychiatry 2004; 75 Suppl 3: iii35-39. 7. Hsu SS, Groleau G. Tetanus in the emergency department: a current review. J Emerg Med 2001; 20(4): 357-365. 8. Farrar JJ, Yen LM, Cook T, et al. Tetanus. J neurol Neurosurg Psychiatry 2000; 69(3): 292-301. 9. Finch RG, Moss P, Jeffries DJ, Anderson J. Toxin-mediated infections. In: Clinical medicine. United Kingdom: Kumar P, Clark M. 2002: 76-77. 10. Okoromah CN, Lesi FE. Diazepam for treating tetanus. Cochrane Database Syst Rev 2004; (1): CD003954. 11. Vaccinatie tegen difterie, tetanus en kinkhoest: vaccinatie van kinderen en adolescenten. Herziening 2013. Hoge Gezondheidsraad België. 12. Vaccinatie tegen tetanus: vaccinatie van volwassenen. Herziening 2013. Hoge gezondheidsraad België. 13. Cooke MW. Are current UK tetanus prophylaxis procedures for wound management optimal? Emerg Med J 2009; 26(12): 845-848. 14. Stubbe M, Swinnen R, Crusiaux A, Mascart F, Lheureux PE. Seroprotection against tetanus in patients attending an emergency department in Belgium and evaluation of a bedside immunotest. Eur J Emerg Med 2007; 14(1): 14-24. 15. Elkharrat D, Sanson-Le-Pors MJ, Arrouy L, Beauchet A, Benhamou F. Evaluation of a bedside immunotest to predict individual anti-tetanus seroprotection: a prospective concordance study of 1018 adults in an emergency department. Emerg Med J 2010; 27(1): 36-42. 16. Stubbe M, Mortelmans LJ, Desruelles D, et al. Improving tetanus prophylaxis in the emergency department: a prospective, double-blind cost-effectiveness study. Emerg Med J 2007; 24(9): 648-653. 17. Blake PA, Feldman RA, Buchanan TM, Brooks GF, Bennett JV. Serologic therapy of tetanus in the United States, 1965-1971. JAMA 1976; 235(1): 42-44.
