tetanus Learning Objectives Introduction Impact of tetanus Clinical features Infection and action

1. Tetanus Angela Houston Angela Houston is a specialist registrar in Infectious disease, microbiology and virology in London and the south coast. Edited by Prof Tom Solomon, Dr Agam Jung and Dr Sam Nightingale • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions This session provides an overview of tetanus - its clinical presentation, differential diagnosis, treatment and prevention.

2. Learning Objectives • By the end of this session you will be able to: • Illustrate the impact of tetanus worldwide, its microbiology and transmission • Describe the actions of tetanus toxin • Recognise the clinical presentation of tetanus and differential diagnosis • Explain the treatment of tetanus • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions

3. Introduction • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions In this session you will learn about the neurological presentation of tetanus, its microbiology, routes of transmission, presentation, treatment and prevention.

4. Impact of Tetanus Worldwide, and Transmission I • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions First described over 3000 years ago, tetanus still causes major health problems in much of the developing world. There are an estimated 800,000 to 1,000,000 deaths worldwide every year despite a safe and effective vaccine being available. Over half of these deaths are in neonates. Worldwide elimination of neonatal tetanus by 1995 was one of the targets of the World Health Organization (WHO), and the number of countries in which neonatal tetanus occurs is progressively decreasing. There are approximately 5-15 cases per year in the UK and these are predominantly in adults aged over 65 (who may have missed vaccination campaigns or have wavering immunity). There are occasional outbreaks in injecting drug users when batches of heroin have become contaminated

5. Impact of Tetanus Worldwide, and Transmission II • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions . Tetanus cases reported worldwide 1990-2004. Ranging from high prevalence (dark red) to very few cases (yellow).

6. Clinical Features • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions The clinical features of tetanus arise from the actions of a potent neurotoxin produced by the obligate Gram positive anaerobic bacteria Clostridium tetini. The toxin blocks the inhibitory action of gamma aminobutyric acid (GABA) to motor neurones, resulting in unopposed motor nerve activity. This causes increased muscle tone, painful muscle spasms and the characteristic 'risus sardonicus' (lock jaw – shown below), and opisthotonus associated with tetanus. Clostridial Clostridial sp. live in the gastrointestinal tract of many mammals including farm animals and horses. The bacteria is able to form spores which are extremely stable and can survive in the soil and environment for long periods of time and are able to withstand many household detergents. Lock jaw in male patient with tetanus

7. Infection and Action of • Tetanus Toxin I • Infection occurs when spores are introduced into the body usually via a deep penetrating wound where the necrotic or anaerobic conditions in the tissues allow the spores to germinate and bacterial growth to occur. • The most common sites are: • Wounds on the lower limbs • Postpartum or post abortion infections of the uterus • Non-sterile intramuscular injections • Compound fractures • Even minor trauma can lead to disease and in up to 30% of patients no portal of entry is apparent. The incubation period is usually between 3-21 days. • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions Micrograph depicting clostridium tetani bacteria that cause tetanus in humans.

8. Infection and Actions of Tetanus Toxin II • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions The bacteria contain a plasmid which encode the toxin. The toxin is a polypeptide which undergoes post translational cleavage to produce an active metalloprotease known as tetanospasmin (tetanus toxin). After death of the clostridial bacterium, the toxin is released and then activated by bacterial or tissue proteases into its active form. This travels through the lymphatic or vascular system until it reaches the neuromuscular junction (NMJ) where it exerts its action. The tetanus toxin is composed of a heavy chain necessary for binding and entry into neurons and a light chain responsible for its toxic properties. At the NMJ the heavy chain of the toxin binds to disialogangliosides (GD2 and GD1b) on the neuronal membrane and is endocytosed into the neurone.

9. Infection and Actions of Tetanus Toxin III • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions It then travels by retrograde axonal transport along the motor neuron from the peripheral to the central nervous system. The active light chain cleaves synaptobrevin which is a protein found in vesicle membranes and is essential for the fusion of synaptic vesicles with the presynaptic membrane. This prevents release the inhibitory neurotransmitter GABA into the synaptic cleft. The α-motor neurons are therefore under no inhibitory control and undergo sustained excitatory discharge causing increased muscle tone, painful spasms, and widespread autonomic instability characteristic of tetanus.

10. Botulism and Tetanus Tetanus toxin is highly homologous in amino acid sequence to the family of botulinum neurotoxins, which like tetanus toxin, inhibits neurotransmitter release by cleavage of proteins involved in vesicle fusion. The difference in clinical symptoms between botulism and tetanus is due to the location of toxin action. Botulinum toxin is not transported to the CNS and remains at the periphery where it inhibits the release of acetylcholine This results in an acute flaccid paralysis. • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions

11. Clinical presentation I • The most common presentation is generalised severe tetanus usually presenting with trismus (lockjaw), intensively painful tonic contractors and signs of autonomic over activity with little or no impairment of conscious level. • Spasms may be triggered by the smallest of stimuli including noise, light or movement. The characteristic signs are: • Opisthotonus • Risus sardonicus (sardonic smile - shown opposite) • Rigid abdomen • Dysphagia • Periods of apnoea due to spasm of thoracic muscles • Recovery requires the growth of new axonal nerve terminals as the tetanus toxin binds irreversibly. This can take weeks to recover. • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions

12. Clinical presentations II • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions • Rarely tetanus can present with localised muscle spasms but this invariably develops into generalised tetanus over time • Neonatal tetanus presents within the first 14 days of life with: • Seizures • Spasms • Trismus • Inability to suck • This is usually caused by contamination of the umbilical stump in mothers who are poorly immunised. An infant with neonatal tetanus

13. Differential diseases and • clinical features I • Drug induced dystonia • Often produces deviation of the eyes, chorioform movements and absence of tonic muscle contractions between spasms. • Tetanus does not produce deviation of the eyes. • Drug induced dystonias may improve with administration of anticholinergic antagonists. • Malignant neurolepitc syndrome • This may present with autonomic instability and muscular spasms but is usually accompanied with a fever and altered mental status. • Trismus due to dental infection • Deep dental root abscess may rarely trigger trismus but usually careful clinical examination can aid diagnosis of this. • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions

14. Differential diseases and clinical features II • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions • Strychnine poisoning • Looks very similar to tetanus • Blood assays available if suspicious • Both require supportive care • Stiff man syndrome • Rare neurological disorder causing severe muscle rigidity and spasms. Antibodies can be detected against glutamic acid decarboxylase (GAD).

15. Treatment of Tetanus • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions • Treatment should usually be carried out in the intensive care unit and involves: • Wound management – careful examination and debridement of necrotic tissue to prevent infection. • Halting toxin production • Neutralisation of unbound toxin • Control of muscle spasms • Management of dysautonomia • Generalised supportive measures

16. Halting Toxin Production • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions Antibiotics act only as an adjunct in the treatment of tetanus as it is a toxin driven disease. Treatment is usually 7-10 days Penicillin and metronidazole are both effective at killing clostridium bacteria although antibiotics have a limited role in the treatment of tetanus. Their is some evidence to suggest that metronidazole may be superior as it may result in the use of fewer muscle relaxants compared to penicillin which has antagonistic effects on GABA

17. Neutralisation of Circulating Toxin • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions Tetanus toxin binds irreversibly to tissue and neurones so only circulating unbound toxin is available for neutralisation. This has been demonstrated in 10% of patients with clinical tetanus Human tetanus immunoglobulin 5000-10,000IU should be given as soon as diagnosis is considered. This is given intramuscularly and required up to 30mls which can cause major discomfort. Normal preparations of immunoglobulin contain reasonable levels of tetanus antibody and can be used as an alternative

18. Active Immunisation/ Tetanus Vaccine • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions Tetanus is one of the few bacterial infections that confers no immunity post infection so all patients should receive active immunisation as soon as a diagnosis is suspected The vaccine is made from a cell free purified toxin extracted form a strain of C. Tetani. This is treated with formaldehyde that confer it into a tetanus toxoid with is absorbed onto an adjunct The vaccine is not live and therefore can be given to immunosuppressed patients. Tetanus vaccine is part iof a combined vaccine given in combination with diphtheria acellular pertussus, polio or Hib B A total of 5 doses at an interval determined by that nation’s immunisation programme should be sufficient to give long term protection.

19. Control of Muscle Spasms Tetanus causes painful muscular spasms which can result in life threatening respiratory compromise and exhaustion. Spasms can be triggered by any stimuli including light/sound and movement. Nursing in a quiet calm environment is paramount to treatment. Benzodiazepines are the mainstay of treatment in terms of muscle relaxants and sedations an frequently require very large doses for long periods. Muscle relaxants when sedation is inadequate neuromuscular blocking agents such as baclofen can be used. Magnesium sulphate is given as an iv infusion and can reduce cardiovascular instability and significantly reduces the need for sedation. • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions

20. Supportive Treatment • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions Since patients with tetanus recover slowly and often require long periods in the intensive care unit ventilated, the majority of treatment is supportive. Supportive care Early tracheostomy, total parental nutrition, fluid balance, prophalaxysis against thrombo-embolism and physiotherapy along with protection against opportunistic infections. Prognosis In developing world the case fatality ranges between 8-30% Neonatal mortality was universal but now rates are between 10-60%. Those with severe disease and short incubation tend to do worse and are often left with long term neurological problems.

21. Key points • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions • Tetanus is a rare but severe neurological infection caused by a toxin produced by the anaerobic bacteria Clostridium tetani • The toxin binds irreversibly to the neuromuscular junction travels by retrograde axonal transport to the central nervous system • The toxin blocks the inhibitory action of GABA to motor neurones • This results in unopposed motor nerve activity which causes increased muscle tone and painful muscle spasms with normal conscious level • Recovery takes weeks as it requires the growth of new axonal nerve terminals • The mainstay of treatment is debridement of wounds and supportive measures to reduce muscle spasms using benzodiazepines and iv magnesium and respiratory support

22. Summary • Having completed this session you will now be able to: • Illustrate the impact of tetanus worldwide, microbiology and transmission • Describe the actions of tetanus toxin • Recognise the clinical presentation of tetanus and differential diagnosis • Explain the treatment of tetanus • Further Reading • Cook, T., R. Protheroe, and J. Handel, Tetanus: a review of the literature. British Journal of Anaesthesia, 2001. 87(3): p. 477-487. • Montecucco, C. and G. Schiavo, Mechanism of action of tetanus and botulinum neurotoxins. Molecular microbiology, 1994. 13(1): p. 1-8. • Cooke, M., Are current UK tetanus prophylaxis procedures for wound management optimal? Emergency Medicine Journal, 2009. 26(12): p. 845. • Attygalle, D. and N. Rodrigo, Magnesium as first line therapy in the management of tetanus: a prospective study of 40 patients*. Anaesthesia, 2002. 57(8): p. 778-817. • Beeching, N. and N. Crowcroft, Tetanus in injecting drug users. British Medical Journal, 2005. 330(7485): p. 208. • Acknowledgements • Centers for Disease Control Public Health Library • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions

23. Question 1 Select the single best answer from the options given. Click on the answer to see if it is correct and read an explanation. • tetanus • Learning Objectives • Introduction • Impact of tetanus • Clinical features • Infection and action • Botulism and tetanus • Clinical presentation • Differential Diagnosis • Treatment • Halting toxin production • Immunisation • Supportive treatment • Key Points • Summary • Questions With regards to the tetanus toxin which statement is INCORRECT? The toxin is encoded on the clostridium tetani chromosome The toxin acts as a metalloprotease The heavy chain is responsible for binding to the neuromuscular junction The toxin travels by retrograde axonal transport to reach the central nervous system