Kansas Journal of Medicine 2007 : The Forgotten Disease

Tetanus: The Forgotten Disease Boutros El-Haddad, M.D. 1 Jill Hanrahan, M.D. 1 1,2 Maha Assi, M.D. 1University of Kansas School of Medicine – Wichita Department of Internal Medicine 2Infectious Disease Consultants, Wichita, KS

Introduction Tetanus was well known to the ancient tetanus immunoglobulin were given physicians of Egypt and Greece, but since intramuscularly and active immunization institution of the active immunization in was started. Although there was no active 1940, it has become an old forgotten disease wound infection, the patient was started on in developed countries. 1 Tetanus is a intravenous metronidazole. Muscle spasms nervous system disorder characterized by and rigidity were controlled with a prolonged contraction of the skeletal scheduled dose of intravenous diazepam. muscles. The disease is caused by Over the next three weeks, the patient’s tetanospasmin, a produced by the symptoms gradually improved, and she was anaerobic bacterium tetani. discharged to a skilled nursing facility.

Case Report Epidemiology A 74-year-old Caucasian female The incidence of tetanus in developed presented to the emergency department countries dropped dramatically since 1940 complaining of trismus. The patient had not mainly due to the widespread use of active been evaluated by a physician for several immunization. 1 Better hygiene and wound years. Her symptoms started 10 days prior care also have played a major role. The with difficulty opening her mouth, annual incidence of tetanus in the US has generalized muscle stiffness, and episodic fallen from 4 to 0.2 per million since 1947. 1 muscle spasms. She denied fever and chills, The decline in incidence was accompanied was not taking any medications, and had no by a decrease in mortality from 50 to 30%. history of or illicit drug use. She did Between 1998 and 2000, the annual not remember ever receiving tetanus incidence of tetanus was 0.16 cases/million vaccination. representing an average of 43 cases per On physical examination, the patient was year. 2 The majority of cases were in patients unable to open her mouth more than 1 cm older than 60 years, reflecting the waning of and the masseter muscle was contracted. immunity with age or inadequate She had a generalized increase in muscle immunization of the elderly. 1 Injection drug tone and episodic painful muscle spasms abuse and the increase of non-immunized involving the entire body. Multiple scars immigrants are responsible for most cases of in different healing stages over the lower tetanus in younger individuals aged 25 to 59. extremities had been caused by scratches According to the CDC 2, 15% of cases of from her 13 cats. tetanus in the US occurred in intravenous The diagnosis of generalized tetanus was drug users. suspected. Five hundred units of human

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Acute injuries account for 70 to 80% of increased muscle tone and painful spasm. US cases; 23% of cases are associated with The also is chronic decubitus ulcers, gangrene, burns affected, manifested by a hypersympathetic and abcesses. 1 About 7% of cases have no state due to failure to inhibit the adrenal apparent source. Neonatal tetanus is rare in release of . Tetanospasmin the US. 1,2 interferes with pre-synaptic acetylcholine Tetanus is common in developing release at the and countries. The worldwide incidence is about disinhibits sympathetic reflexes at the spinal 1,000,000 cases per year. 3,4 It is a major level.1 The inhibitory effect of cause of death especially in neonates. tetanospasmin is irreversible. Recovery Tetanus accounted for 300,000 deaths in requires the growth of new axonal nerve 2000, including 200,000 neonatal deaths.5 terminals in 4 to 6 weeks. produces another called Pathogenesis and Pathology that apparently has no pathogenic role. 1 Clostridium tetani is an obligatory gram positive anaerobic bacillus. The bacteria are Clinical Features usually found in contaminated soil and The incubation period of tetanus usually animal gut in the sporiform phase. When lasts between 3 and 21 days with a range of these spores contaminate a wound, they one day to several months. 1 A correlation germinate under anaerobic conditions, exists between the distance of the injury transform into a rod-shaped bacterium, and from the CNS and the duration of the produce tetanospasmin. Tetanospasmin is incubation period.1,5 The closer the distance, an produced by mature bacteria, the shorter the incubation period. Both the then cleaved intracellularly into light and incubation period and the time of onset heavy chains before . The heavy (time from the first symptom to the first chain appears to mediate binding to cell generalized spasm) inversely correlate with surface and transport , while the prognosis.1 light chain is responsible for the clinical Tetanus has four clinical forms: manifestations of tetanus. 1 generalized, localized, cephalic, and After its excretion, tetanospasmin gains neonatal. Generalized tetanus is the most entry into the (CNS), common and severe. The generalized form both locally and distally, via the presynaptic typically starts with spasm of the masseter terminals of lower motor neurons. muscles, causing trismus or “lockjaw” and Tetanospasmin is transported intra-axonally increased tone of the orbicularis oris in a retrograde fashion to the cell body, the resulting in the characteristic “risus ventral horns of the spinal cord, and to the sardonicus”. The patient experiences diffuse motor nuclei of the cranial nerves where it spasms involving muscle groups in the neck, exerts its major pathogenic action. After back, abdomen, and extremities. These reaching the spinal cord and the brain stem, spasms are painful, intermittent, and tetanospasmin binds tightly and irreversibly unpredictable. They often are triggered by to specific receptors, inhibiting the release noise and light. of inhibitory ( and Patients with generalized tetanus γ-amino-butyric acid) from presynaptic typically have symptoms of autonomic inhibitory neurons. overactivity that manifest as sweating, The net effect is the disinhibition of tachycardia, cardiac arrhythmia, labile motor excitatory neurons resulting in or , and fever.

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Respiratory muscles also are affected Differential Diagnosis causing periods of apnea. During poisoning may produce a generalized tetanic spasms, patients clinical syndrome similar to tetanus. characteristically clench their fists, arch their Toxicologic screen of urine and blood back, flex their arms while extending their should be performed if a suspicious injection legs, and become apneic. 1 Death is due to is suspected or the history is not typical for respiratory failure or to autonomic tetanus (e.g., no injury or adequate dysfunction. Recurrent tetanus may occur if immunization). The treatment of tetanus the patient is not immunized since the and strychnine poisoning is similar. infection does not confer immunity. Trismus due to dental infection may be Recovery is typically 2 to 6 weeks. confused with cephalic tetanus. Drug Localized tetanus is usually a prodrome induced dystonia and malignant neuroleptic of the generalized form. It presents with syndrome can mimic tetanus. localized rigidity and spasm of a muscle group near the site of injury. Subsequently, Treatment patients develop generalized tetanus. In The treatment of patients with tetanus some cases, localized disease reflects partial requires a multidisciplinary approach in the immunity with resolution of the spasms intensive care unit.1 The mainstay of without generalization. 6 Cephalic tetanus is treatment consists of eliminating the source a form of localized tetanus involving the of toxin production, neutralizing unbound cranial nerves in a patient with head and toxin, and managing symptoms and neck injuries. 1 complications. Neonatal tetanus is related to the inadequate use of aseptic techniques in non- Halting toxin production immunized mothers. It usually occurs Wound debridement is important to within 14 days after birth. 1,7 Infants present eliminate the source of toxin production. with generalized weakness and failure to All foreign bodies, including spores and nurse, followed by rigidity and spasms. necrotic tissue, should be removed. Mortality exceeds 90%. Apnea and sepsis Metronidazole and penicillin G are the drugs are the leading causes of death. of choice, but studies have shown better outcomes with metronidazole. 1,8 Intravenous Diagnosis metronidazole should be given initially at a The diagnosis of tetanus is based on dose of 15mg/kg followed by 20 to 30 clinical symptoms and a high index of mg/kg/day intravenously for 7 to 14 days or suspicion in susceptible individuals.1 until there is no visible sign of active local Anaerobic cultures from the wound are infection.1 Alternatives include cefazolin, usually negative. A positive culture does cefuroxime, and ceftriaxone. not confirm the diagnosis. Anti-tetanus are undetectable in the majority Neutralizing of unbound toxin of patients with tetanus. However, the Tetanospasmin is bound irreversibly to presence of antibodies at low titer does not tissues and only unbound toxin is available confer immunity and cannot be used to rule for neutralization. Passive immunization out the disease. Electroencephalography with human tetanus immune globulin and electromyography can be helpful in (HTIG) shortens the course of tetanus and ruling out other conditions. improves survival. A dose of 500 units of

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HTIG should be given intramuscularly as daily to assess the patient’s progress, and to soon as the diagnosis of tetanus is observe for possible complications. considered. 1,9 The use of intrathecal HTIG is Intrathecal baclofen was found to control not indicated.1 spasms and rigidity in a few small studies.10

Management of muscle spasms Management of autonomic instability Generalized spasms are life threatening. Magnesium sulfate is effective in the Patients should be placed in a quiet dark treatment of autonomic dysfunction in room to avoid provoking muscle spasms. patients with tetanus.1,11 It also has a Spasms can cause exhaustion when severe. potential role in controlling muscle spasms. Benzodiazepines are the mainstay in the Magnesium sulfate blocks cathecholamine symptomatic therapy of tetanus. They are release from the nerves and reduces receptor usually effective in controlling muscle responsiveness to cathecholamine. spasms, and patients may benefit from their Labetolol (0.25 to 1 mg/min) could be amnestic effect. These drugs are gamma- used because of its dual alpha and beta aminobutyric acid (GABA) agonists. They blocking properties.1 Beta blockade alone have the potential of antagonizing the effect should be avoided because the resulting of the toxin. unopposed alpha effect may produce severe Treatment with diazepam, lorazepam, hypertension and even death. Other useful and midazolam appear to be equally agents include morphine sulfate by effective. Oral administration of these drugs continuous intravenous infusion, atropine, is possible, but some patients do not absorb and clonidine. the drugs well and develop gastrointestinal motility disorders. Diazepam 10 to 30 mg Supportive Care intravenously is the usual starting dose. The Patients with tetanus are at risk of intravenous formulation of diazepam and respiratory failure and aspiration. Many lorazepam contains propylene glycol that require endotracheal intubation to maintain can cause lactic acidosis at high doses. adequate ventilation and preserve the Intravenous midazolam does not contain airway.1 Early tracheostomy usually is propylene glycol, but must be given as a preferred in patients with tetanus who continuous infusion of 5 to 15 mg/hour. develop respiratory failure because of the Intravenous propofol infusion is likelihood of prolonged mechanical effective in controlling spasms and rigidity. ventilation. It is expensive and associated with lactic Nutritional support should be started as acidosis, hyper-triglyceridemia, and soon as possible because energy demands pancreatic dysfunction.1 and requirements are very high. Neuromuscular blocking agents can be Physical therapy should be started as soon as used in severe cases. Pancuronium the spasms have ceased. (intermittent injection) and the shorter acting vancuronium (continuous injection) are Active Immunization usually used. Vancuronium is preferred Tetanus is one of the rare bacterial over pancuronium because of the worsening infections that do not confer immunity of autonomic instability observed with the following recovery. All patients with latter. Both agents should be used tetanus should receive active immunization cautiously and the patient should be sedated with three doses of tetanus and diphtheria adequately. These agents should be stopped spaced at least two weeks apart, with

12 Kansas Journal of Medicine 2007 Tetanus: The Forgotten Disease the first dose administered upon diagnosis. Tdap previously. For adults previously It should be presumed that patients who are vaccinated with Tdap, Td should be used if a inadequately immunized to tetanus are tetanus -containing vaccine is inadequately immunized to diphtheria as indicated for wound care. Adults who have well. 12 Subsequent doses should be given at completed the 3-dose primary tetanus 10-year intervals throughout adulthood. vaccination series and have received a tetanus toxoid-containing vaccine less than Prophylaxis five years earlier are protected against Tetanus is a preventable disease. 1 A tetanus and do not require a tetanus toxoid- series of three monthly intramuscular containing vaccine as part of wound injections of tetanus toxoid provides management. adequate immunity for at least 5 years. Persons with unknown or uncertain Patients younger than 7 years of age and tetanus vaccination histories should be those never immunized to pertussis should considered to have had no previous tetanus receive the combined diphtheria-tetanus- toxoid-containing vaccine. Persons who pertussis vaccine (Tdap). Tetanus-diphteria have not completed the primary series might (Td) booster injections are indicated every require tetanus toxoid and passive 10 years. Mild reaction to tetanus toxoid is vaccination with TIG at the time of wound common including local tenderness, edema, management (see Table 1). When both TIG and low grade fever. Severe reactions are and a tetanus toxoid-containing vaccine are rare. Guillain-Barre syndrome was linked to indicated, each product should be tetanus toxoid in some reports but this was administered using a separate syringe at not confirmed in subsequent epidemiologic different anatomic sites. Adults with a analysis. 1 history of Arthus reaction following a The CDC 13 has recommended adminis- previous dose of a tetanus toxoid-containing tering tetanus toxoid-containing vaccine and vaccine should not receive a tetanus toxoid- tetanus immune globulin (TIG) as part of containing vaccine until at least 10 years standard wound management to prevent after the most recent dose, even if they have tetanus (see Table 1). Tdap is preferred to a wound that is neither clean nor minor. In Td for adults vaccinated less than five years all circumstances, the decision to administer earlier who require a tetanus toxoid- TIG is based on the primary vaccination containing vaccine as part of wound history for tetanus (see Table 1). management and who have not received

Table 1. Recommendation for use of tetanus prophylaxis in wound management. Clean, minor wounds All other wounds Immunization with tetanus toxoid Tetanus toxoid Immunoglobulin Tetanus toxoid Immunoglobulin

Unknown or less than Yes No Yes Yes three doses Three or more doses No, unless >10 No No unless > 5 No years since last years since last dose dose

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References 1 Bleck TP. Clostridium tetani (tetanus). 8 Ahmadsyah I, Salim A. Treatment of In: Mandell GL, Bennett JE, Dolin R, tetanus: An open study to compare the eds. Principles and Practices of Infectious efficacy of procaine penicillin and Disease. 6th edition. Vol 2. Philadelphia: metronidazole. Br Med J (Clin Res Ed) Churchill Livingstone, 2005: 2817–2822. 1985; 291:648-650. 2 Pascual FB, McGinley EL, Zanardi LR, 9 Blake PA, Feldman RA, Buchanan TM, Cortese MM, Murphy TV. Tetanus Brooks GF, Bennett JV. Serologic surveillance - United States, 1998-2000. therapy of tetanus in the United States. MMWR Surveill Summ 2003; 52:1-8. JAMA 1976; 235:42-44. 3 Thwaites Farrar JJ. Preventing and 10 Santos ML, Mota-Miranda A, Alves- treating tetanus. BMJ 2003; 326:117- Pereira A, Gomes A, Correia J, Marcal N. 118. Intrathecal baclofen for the treatment of 4 Bhatia R, Prabhakar S, Grover VK. tetanus. Clin Inf Dis 2004; 38:321-328. Tetanus. Neurol India 2002; 50:398-407. 11 Thwaites CL, Yen LM, Loan HT, et al. 5 Vandelaer J, Birmingham M, Gasse F, Magnesium sulphate for treatment of Kurian M, Shaw C, Garnier S. Tetanus in severe tetanus: A randomised controlled developing countries: An update on the trial. Lancet 2006; 36:1436-1443. Maternal and Neonatal Tetanus 12 McQuillan GM, Kruszon-Moran D, Elimination Initiative. Vaccine 2003; Deforest A, Chu SY, Wharton M. 21:3442-3445. Serologic immunity to diphtheria and 6 Risk WS, Bosch EP, Kimura J, Cancilla tetanus in the United States. Ann Intern PA, Fischbeck KH, Layzer RB. Chronic Med 2002; 136:660-666. tetanus: Clinical report and 13 Kretsinger K, Broder KR, Cortese, MM, histochemistry of muscle. Muscle Nerve et al. Preventing tetanus, diphtheria, and 1981; 4:363-366. pertussis among adults: use of tetanus 7 Traverso HP, Bennett JV, Kahn AJ, et al. toxoid, reduced diphtheria toxoid and Ghee application to the umbilical cord: A acellular pertussis vaccines. MMWR risk factor for neonatal tetanus. Lancet Recomm Rep 2006; 55 (RR17): 1-33. 1989; 1:486-488. Keywords : tetanus, Clostridium tetani, case report

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