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Botulism BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Angela Houston Dr Angela Houston is a specialist registrar in Infectious Diseases, Microbiology and Virology in London/ South Coast. This session provides an overview of botulism. Clinical presentation, differential diagnosis, treatment and prevention. Edited by Prof Tom Solomon and Dr Agam Jung Learning Objectives BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions By the end of this session you will be able to: • State the impact of botulism worldwide, microbiology and transmission • Describe the actions of botulinum toxin • Recognise the clinical presentation of botulism and differential diagnosis • Specify the laboratory and clinical diagnosis of botulism • Explain the treatment of botulism Overview BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions In this session you will learn about the neurological presentation of botulism. You will learn about the microbiology, routes of transmission, presentation, treatment and prevention of botulism and infections caused by bacterial neurotoxins. Botulism Microbiology I BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Botulism is a rare and potentially fatal disease caused by a highly potent neurotoxin released by the anaerobic spore forming bacterium Clostridium botulinum and, rarely by Clostridium baratii and Clostridium butyricum. There are seven neurotoxins (A-G). Illness in humans is usually caused by types A, B or E, or rarely by F. All toxins block the release of acetylcholine at the neuromuscular junction and produce the same neurological syndrome. Clostridium botulinum is present in the soil and environment and is responsible for three naturally occurring forms of botulism, all of which present with the same neurological features but depend on mode of acquisition. Botulism Microbiology II BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Clostridium botulinum – CDC Public Health Image Library #2107 Transmission BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Botulism can be transferred by: • • • Food-borne from ingestion of contaminated food with preformed toxin Infantile botulism caused by ingestion of spores which colonise the gastrointestinal tract and produce toxin in vivo Wound botulism caused by infection of a wound with Clostridium botulinum and production of toxin in vivo There is also a further possibility that botulism may occur as a result of deliberate release or as accidental exposure following miss-injection of therapeutic neurotoxin. The neurological syndrome produces acute, symmetrical descending flaccid paralysis. Types: Food-borne Botulism BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Food-born botulism occurs from ingestion of preformed toxin present in food which has been stored in airtight (anaerobic) conditions. Cases have mainly occurred in sporadic outbreaks and the Health Protection Agency (HPA) reports 33 cases in the UK between 19802006 of which there were three fatalities. Recent cases have occurred amongst Polish immigrants who eat home preserved sausages and pickles stored in jars. Very rarely, intestinal colonisation similar to infant botulism occurs in adults, usually with an underlying reason, such as gastrointestinal abnormalities. Prodromal symptoms begin within hours of ingesting the preformed toxin. Types: Infantile Botulism BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Gastrointestinal colonisation occurs when babies ingest environmental spores of Clostridium botulinum which germinate within the gastrointestinal tract producing in vivo toxin production. Babies present anytime from 1 week to 12 months of age (usually < 6 months) with non specific symptoms including: • • • • • • • • Weakness Hypotonia Hyporeflexia Bulbar palsies Constipation Poor feeding Dehydration Disease progression in children can be very rapid. The disease presentation is variable and is likely to reflect the differences in bacterial load and host immunity in infants of different ages. Only six infantile cases have been reported to the HPA from 19752006 with no fatalities. Types: Wound Botulism BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Wound botulism was first described in the USA in the 1950s but the last decade has seen a huge increase in the number of cases and now is the most common form of botulism seen in the developed world. 163 cases have been reported to the HPA in the UK from 2000-2009 reflecting the increase in intravenous drug use (IVDU). The disease is seen almost exclusively in injecting heroin users who use 'skin popping' as a route of drug administration. Types: Drug Use BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Heroin used in the UK originates predominantly from Asia and arrives as a powder which has undergone a number of processing steps including 'cutting' with bulking agents en route. Any of these stages may result in the accidental introduction of clostridium botulinum spores from contaminated material. In order to inject the drug, it is mixed with an acid usually citric acid and heated briefly. In IVDUs with limited venous access the material is injected directly into the skin or muscle ('skin popping'). The acid results in local necrosis which produces anaerobic conditions ideal for germination of Clostridium botulinum and toxin production. It is not seen in IVDUs who inject directly into veins as the spores do not have time to germinate in anaerobic conditions. Actions of Botulinum Neurotoxin I BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Regardless of mode of entry to the human body, the neurotoxin disseminates widely in throughout the vascular system and binds irreversibly to the presynaptic sides of peripheral cholinergic synapses at ganglia and neuromuscular junction. Actions of Botulinum Neurotoxin II BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions The heavy chain of the toxin binds to the receptors, allowing the light chain to translocate into the nerve cell via receptor mediated-endocytosis. Inside the cytoplasm, the toxin produces an irreversible disruption in stimulation-induced acetylcholine release by that presynaptic nerve terminal. Recovery Recovery is slow as new synaptic terminals must form from the original nerve plate, a process that takes approximately six months. Adrenergic nerves are unaffected and the toxin seems unable to cross the blood brain barrier so limiting damage to the peripheral cholinergic system. If onset is very rapid, there may be no symptoms before sudden respiratory paralysis occurs. Clinical Presentation of Botulism BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Presentation Adults patients infected with the botulinum neurotoxin present with similar clinical features irrespective of mode of acquisition: • Bilateral cranial nerve palsies • Descending flaccid paralysis • Blurred or double vision • Dysphagia and a dry mouth (often the first complaints) progressing to a symmetrical flaccid paralysis and respiratory failure Differential Diagnosis I BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions The following are diseases with similar clinical features to botulism: • Botulism • Guillain–Barre syndrome (GBS) • Miller Fisher variant of GBS • Myasthenia gravis • Viral encephalitides • Tick paralysis • Paralytic shellfish poisoning • Rabies Differential Diagnosis II Botulism BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions • • • • • Acute bilateral cranial neuropathies and symmetrical descending weakness No fever unless intercurrent infection Only sensory deficit may be blurred vision History of exposure – ingestion IDU or a traumatic wound Guillain-Barre syndrome (GBS) • • • • • • Antecedent febrile illness Ascending symmetrical paralysis Loss of sensation, parasthesia, pain, loss of reflexes Electromyograph may help differentiate Antiganglioside antibody may be elevated in CSF or serum with GBS or Miller Fisher No augmentation of modified action potential with repetitive nerve stimulation at 20-50 Hz in contrast to botulism Differential Diagnosis III Miller Fisher variant of GBS BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions • • • • Antecedent febrile illness Ascending paralysis and parasthaesia Early loss of reflexes Internal and external opthalmoplegia with ataxia which is more marked than limb weakness Myasthenia gravis • • • • • • • • Muscular fatigability Resolution of paralysis with Tensilon (but some improvement seen in some cases of botulism) Recurrent paralysis Sustained response to anticholinesterase therapy Spinal/paralytic poliomyelitis, almost never sensory loss Antecedent febrile illness, asymmetrical paralysis Altered CSF Meningeal irritation Differential Diagnosis IV Viral encephalitides BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions • • • • • • • Fever and altered mental state Abnormal CSF Asymmetric weakness EEG findings Cerebrovascular accident Sensory deficits Asymmetric hyperactive deep tendon reflexes Tick paralysis • • • • • • • Travel to endemic area (Australia, USA) Presence of femal tick, may be hidden in long hair Parasthesia of affected extremities Ascending paralysis Loss of deep tendon reflexes Rare cranial nerve involvement Occasional cerebellar ataxia Differential Diagnosis V Paralytic shellfish poisoning BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions • • • • • • History of consumption of shellfish (or rarely fish) Incubation of 1 hour Numbness of face and lips Parasthesis Normal reflexes Respiratory paralysis Rabies • • • • • Not necessarily following a recent bite Can be months Ascending paralysis Incoordination Pharyngeal spasm particularly on drinking buy not due to a breeze of air Laboratory and Clinical Diagnosis of Botulism I BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Diagnosis The diagnosis of botulism is based on clinical suspicion. Learning Bite: Always seek advise from an Infectious diseases specialist and ITU. Demonstration of the toxin in serum can be helpful. Laboratory and Clinical Diagnosis of Botulism II BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Food-borne botulism • In food-borne botulism, toxin is present in serum or faeces in >50% of cases within one day of onset, but <25% after 3 days • C. botulinum will be present in the faeces for longer which may be helpful diagnostically • Toxin can be isolated in faecal samples in >70% of cases within 2 days and 40% 10 days after onset of food poisoning Laboratory and Clinical Diagnosis of Botulism III BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Wound botulism • In wound botulism, toxin is isolated in the blood in 40% of suspected cases • It is important to very carefully examine patients for wounds that may need debridement no matter how small • Toxin detection requires 10ml serum sample (ideally before any antitoxin is administered). This is measured by a bioassay in mice. The presence of toxin confirms the clinical diagnosis • Serum samples are not so helpful in infantile botulism The Treatment of Botulism I BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Treatment of botulism should include: • • • • Early administration of botulinum antitoxin (if indicated) Search for and debride any wound no matter how trivial Give antibiotics if wound present Supportive treatment The Treatment of Botulism II Antitioxin BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Antitoxin is an effective treatment and will prevent further progression of symptoms but will not reverse established paralysis. •If administered early it may neutralise any circulating toxin •There are a number of antitoxin products available all of which have been derived from pooled animal immunoglobulin •If the patient continues to deteriorate the dose may be repeated within 24 hours •Since antitoxin is derived from animal immunoglobulin it carries a risk of allergic reactions such as anaphylaxis and serum sickness The Treatment of Botulism III BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions With antitoxin and good supportive treatment, recovery is to be expected although it may take weeks or months, so prolonged hospital admissions are likely. Learning Bite: Any case of suspected Botulism should be reported promptly to the HPA. Key Points BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions • Botulism is a rare but potentially life threatening disease caused by neurotoxins of Clostridium botulinum • Three endogenous forms exist. Food-bourne, infantile and wound botulism which is now the commonest form seen with the rise in intravenous drug users • Botulinum toxin binds irreversibly to the presynaptic membrane at the motor endplate inhibiting release of acetylcholeine • Classically presents with bilateral cranial nerve palsies and an acute, symmetrical, descending flaccid paralysis in the absence of fever or cognitive disturbance • Diagnosis is clinical but can be aided by identifying Botulinum toxin in serum or stool samples • Treatment is supportive and antitoxin can be effective in preventing further progression if given early. Wounds infected with C. Botulinum need urgent debridement and antibiotic treatment Summary BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Having completed this session you will now be able to: • State the impact of botulism worldwide, microbiology and transmission • Describe the actions of botulinum toxin • Recognise the clinical presentation of botulism and differential diagnosis • Specify the laboratory and clinical diagnosis of botulism • Explain the treatment of botulism References and further reading BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions • Montecucco, C. and G. Schiavo, Mechanism of action of tetanus and botulinum neurotoxins. Molecular microbiology, 1994. 13(1): p. 1-8. • Brett, M., G. Hallas, and O. Mpamugo, Wound botulism in the UK and Ireland. Journal of medical microbiology, 2004. 53(6): p. 555. • Cherington, M. Botulism: update and review. 2004: [New York]: Thieme-Stratton Inc.,[c1981]. • McLauchlin, J., K. Grant, and C. Little, Food-borne botulism in the United Kingdom. Journal of Public Health, 2006. 28(4): p. 337. • Lindstrom, M. and H. Korkeala, Laboratory diagnostics of botulism. Clinical microbiology reviews, 2006. 19(2): p. 298. • Bleck, TP. Clostridium botulinum (botulism). In: Principles and Practice of Infectious Diseases, 6th ed. Mandell, GL, Bennett, JE, Dolin, R, (Eds), Churchill Livingstone, Philadelphia, PA 2005, p. 2822. • Health Protection Agency Website. • Antitoxin and advice are available from the duty doctor at the Health Protection Agency, Centre for infections in the UK. For infant botulism a human derived Botulinum immune Globulin BabyBIG® is available from the Infant Botulism Treatment and Prevention Program (IBTPP) California USA. Question 1 BOTULISM • • • • • • • • • • • • • • Learning Objectives Overview Microbiology Transmission Types of Botulism Actions of the toxin Clinical features Differential diagnosis Investigations Treatment Key points Summary References and further reading Questions Which of the statements are correct with regards to the botulinum toxin? a) Botulinum toxin is one of the most potent neurotoxins known b) Botulism is most commonly caused by the Botulinum neurotoxins A and C c) Causes inhibition of the action of GABA d) Affects the peripheral and central nervous system