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Botulism
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Botulism Stephen J. Aston, Nicholas J. Beeching
KEY FEATURES • Rare neuroparalytic illness caused by potent neurotoxins produced by Clostridium botulinum. • Typically presents with bilateral cranial nerve palsies followed by symmetric descending flaccid paralysis and occasional progression to respiratory muscle weakness. • Clostridial spores are ubiquitous in the environment, and botulism is presumed to occur worldwide but under-reporting is significant. • Several naturally occurring forms are recognized: food-borne botulism, wound botulism, infant botulism, and adult intestinal toxemia botulism. • Food-borne disease remains a significant problem in countries where home preservation of food is popular. • Wound botulism has increased in recent years due to an epidemic among people who inject drugs. • Early administration of antitoxin and the prompt recognition of respiratory compromise, allowing the timely implementation of ventilatory support, are key to optimizing outcome.
that produce neurotoxin. After absorption and hematogenous dissemination, botulinum toxin exerts its effects at the presynaptic terminals of cholinergic nerve junctions by blocking neurotransmitter release. Several naturally occurring forms of human botulism are recognized: food-borne botulism, wound botulism, infant botulism, and adult intestinal toxemia botulism. Iatrogenic botulism has been reported after the direct inoculation of concentrated botulinum toxin preparations for cosmetic purposes. Intoxication after absorption of toxin across the respiratory mucosa, termed inhalational botulism, is also recognized.
EPIDEMIOLOGY Attempts to describe the global epidemiology of botulism are hampered by the lack of detailed incidence data. The necessary public health infrastructure to detect and report cases is lacking in many countries, and few case reports have been published.4 In particular, there is a near-complete absence of data from subSaharan Africa.5 Because C. botulinum spores are ubiquitous in the environment, it is presumed that cases occur globally, although rates may vary with dietary customs and food handling practices.
Food-Borne Botulism INTRODUCTION Botulism is a rare, naturally occurring, neuroparalytic illness caused by potent neurotoxins produced by Clostridium botulinum and, rarely, other Clostridium species. It manifests as a characteristic syndrome of symmetric cranial nerve palsies followed to a varying extent by symmetric descending paralysis of voluntary muscle that can progress to respiratory compromise and death. Botulinum spores are ubiquitous in the natural environment, and cases occur worldwide, although are probably greatly under-reported. The first complete clinical description of botulism was published by Kerner in 1822, who termed the disease sausage poisoning, having observed outbreaks associated with the consumption of spoiled meat. The early 20th century saw a massive rise in cases of botulism due to the increasing popularity of food canning, particularly home-made preparations in sealed glass jars. After the elucidation of its mechanism of action in the mid-20th century, the potential therapeutic use of botulinum toxin has been exploited.1–3
Food-borne botulism is caused by consumption of food contaminated with pre-formed botulinum toxin. It is usually associated with uncooked food products, as heating food to >85°C for more than 5 minutes inactivates toxin. Although botulinum spores may potentially contaminate many foodstuffs, germination and toxin production only occur when spores are incubated in an anaerobic, low-salt milieu at greater than 4°C. The processes of canning and fermentation of foods are particularly conducive to producing such conditions. Although effective methods of inactivating spores were introduced in the early 20th century, outbreaks of food-borne botulism attributable to commercially canned foods still account for a substantial proportion of cases in Eastern Europe, and a recent outbreak has been reported in the United States.6 Homecanned foods remain a major source of intoxication, and food-borne botulism occurs with high incidence in areas where home preservation of food is popular, such as Eastern Europe and the Southern United States.7 Several outbreaks in prisons due to illicit alcoholic brew containing fermented vegetables have recently been reported.8 There is an exceptionally high incidence of food-borne botulism in Alaska and some areas of Canada attributable to the consumption of fermented aquatic mammal meat.9
NATURAL HISTORY, PATHOGENESIS, AND PATHOLOGY
Wound Botulism
C. botulinum are anaerobic, gram-positive, spore-forming bacilli that are found in soils and aquatic sediments. Strains of C. botulinum are classified into seven types, designated A to G, according to the antigenic properties of the botulinum toxin they produce. Human botulism is caused by types A, B, E, and rarely type F. Some strains of C. baratii and C. butyricum can also produce botulinum neurotoxin and have been implicated in human disease. The spores of C. botulinum are highly resistant. Under appropriate conditions, they germinate to release vegetative organisms
Wound botulism follows the absorption of toxin produced by organisms contaminating a wound site, so clinical incubation periods are longer than for botulism caused by food, which contains pre-formed toxin. Cases have increased in developed countries in recent years, driven by an epidemic among injecting drug users and strongly associated with the practice of injecting into the subcutaneous tissues or muscle, known as skin or muscle popping.10 Sporadic cases of botulism associated with contaminated compound fractures are occasionally reported.
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Infant Botulism Infant botulism is caused by the endogenous production of toxin by C. botulinum that has colonized the infant gastrointestinal tract after the germination of ingested spores.11 Since its first description in 1976, infant botulism has been reported in all continents except Africa. Globally, most reported cases occur in the United States, where between 1976 and 2010, 2803 cases were reported.12 Ingestion of honey, which is often contaminated by C. botulinum spores, was implicated in some cases, but in the majority a definitive source of botulinum spores was not identified. Recently, contaminated corn syrups have also been implicated, but again with no cases definitively attributed to this exposure. In the absence of a definitive source, acquisition is presumed to occur via ingestion of spores adherent to dust particles.
Adult Intestinal Toxemia Botulism Botulism in adults resulting from in vivo toxin production by Clostridia colonizing the gastrointestinal tract was first demonstrated in the 1980s. In the few cases described, there is often a preceding history of gastrointestinal surgery, inflammatory bowel disease, or antimicrobial use that presumably disrupts the normal microbial flora, allowing colonization by Clostridia species.13
CLINICAL FEATURES The clinical presentation of all forms of botulism is dominated by neurologic features resulting from the toxin-induced blockade of voluntary motor and autonomic cholinergic junctions. Symptoms usually appear between 1 and 5 days after ingestion of the toxin, although very high doses may present within a few hours and progress almost immediately to respiratory paralysis. In adults, cranial nerve palsies are almost always the initial presenting symptoms. Extraocular muscle paresis results in blurred or double vision. Marked ptosis is usually evident, and pupillary responses may also be depressed. The face may appear expressionless as a consequence of bilateral facial nerve dysfunction. Involvement of lower cranial nerves causes dysphonia, dysarthria, and dysphagia. Early autonomic involvement causes anhidrosis, leading affected individuals to complain of extremely dry and often painful, mouth, tongue, and throat. Disease progression manifests as a symmetric, flaccid, descending paralysis of voluntary muscles associated with loss of deep tendon reflexes. Involvement of the diaphragm and accessory thoracic muscles may result in respiratory compromise and death unless supportive care is provided. Due to the generalized lack of motor function, respiratory failure often occurs without apparent features of respiratory distress and may be overlooked until very advanced. Significant pharyngeal muscle weakness causing airway compromise may necessitate intubation and ventilation even in the absence of respiratory muscle weakness. Progressive autonomic involvement leads to constipation, urinary retention, and hemodynamic dysregulation. Fever is usually absent, except in some cases of wound botulism, when it probably indicates concurrent wound infection with other bacteria. Sensory nerves are unaffected by botulinum toxin. Similarly, there is no effect on level of consciousness or cognitive function, although the features of expressionless facies and dysarthria are often mistaken for alcohol or drug intoxication. The extent, severity, and rate of progression of clinical features vary, and not all untreated cases progress to respiratory muscle paralysis. Some affected individuals only develop cranial nerve palsies that gradually resolve without any other features of botulism becoming evident. Botulinum toxin binding is irreversible, and recovery of function depends on nerve terminal regeneration. Individuals with respiratory compromise typically require ventilatory support for 2 to 8 weeks, although occasionally recovery is
much more protracted. Fatigue and generalized weakness may persist for many months after recovery, particularly in older patients and those who have been mechanically ventilated.14 In food-borne disease, the neurologic features of botulism may be preceded by abdominal pain, nausea, vomiting, and diarrhea. Such gastrointestinal disturbance has not been reported in wound botulism and probably represents the effect of other bacteria and their toxins co-contaminating the causative improperly preserved food. Clinical effects of botulinum toxin usually become evident 18 to 36 hours after consumption of the implicated foodstuff.
PATIENT EVALUATION, DIAGNOSIS, AND DIFFERENTIAL DIAGNOSIS In the context of a large outbreak, in which multiple patients present with combinations of cranial nerve palsies and subsequent development of descending flaccid paralysis, botulism is easily recognizable. However, it is a rare condition, and the majority of cases occur singularly, meaning that the diagnosis is often delayed or missed altogether. Botulism should be suspected in any adult with acute-onset gastrointestinal, autonomic, and cranial nerve dysfunction. The four “Ds” are the key clues: dysphonia, dysphagia, dysarthria, and descending paralysis. Demonstration of bilateral cranial nerve findings and evidence of neurologic progression increase the level of suspicion. Reported recent consumption of home canned foods or similar illness in family members or close contacts provides further supporting evidence for the diagnosis. Alternatively, features of injecting drug use are highly suggestive. Important differential diagnoses to consider when botulism is suspected include alcohol or drug misuse, Guillain–Barré syndrome (GBS), myasthenia gravis, stroke syndromes, Eaton–Lambert syndrome, and tick paralysis. Table 60.1 includes other differential diagnoses with important distinguishing features. GBS typically presents as an ascending paralysis, and there is often a history of antecedent infection, typically Campylobacter jejuni gastroenteritis. Distinguishing botulism from the triad of ophthalmoplegia, ataxia, and areflexia that characterizes the Miller–Fisher variant is often more difficult. However, in contrast to botulism, areflexia typically precedes the onset of significant muscle weakness in GBS. Fatigable muscle weakness is the hallmark of myasthenia gravis. A marked improvement with administration of edrophonium is highly suggestive of myasthenia gravis, although about 25% of patients with botulism show some response. Patients with Eaton–Lambert syndrome usually have clinically apparent lung cancer, although electromyographic findings are indistinguishable from botulism. The asymmetric weakness and upper motor neuron signs caused by most stroke syndromes should be readily distinguishable from botulism on clinical examination. Tick paralysis causes paresthesia and ascending paralysis; the diagnosis is particularly apparent if the tick is still attached. Cerebrospinal fluid analysis may be useful; protein levels are normal in botulism, compared with GBS where they are typically raised, although this may not be apparent until several days after symptom onset. Electromyography (EMG) may also be helpful. In particular, repetitive stimulation at high frequencies shows facilitation of muscle action potentials in botulism that is not evident in either GBS or myasthenia gravis. EMG is best performed and interpreted by an experienced operator, because results may vary among muscle groups. To avoid false-negative results, it is essential that clinically affected muscle groups are tested. Brain imaging by computed tomography (CT) or magnetic resonance imaging (MRI) should be used to uncover the rare brainstem stroke syndromes that produce symmetric bulbar palsies. Definitive laboratory confirmation of botulism requires the demonstration of toxin in specimens of patient serum, gastric secretions or stool or, in the case of food-borne botulism, a food sample. The standard method for determining botulinum toxin
CHAPTER 60 Botulism
TABLE 60.1 Differential Diagnoses (In Alphabetical Order) Differential Diagnosis
Distinguishing Features
CNS infections
Altered mental status; abnormal CSF; EEG changes
CNS space-occupying lesion
Asymmetric weakness and upper motor neuron signs; abnormal brain imaging
Diabetic neuropathy
Sensory features; limited cranial nerve involvement
Diphtheria
Antecedent pharyngitis; sensory features; associated cardiac complications
Eaton–Lambert syndrome
Similar EMG findings; often evidence of underlying lung cancer
Electrolyte disturbances (e.g., hypermagnesemia)
Abnormal serum electrolytes
Guillain–Barré syndrome
Ascending paralysis with early areflexia; history of antecedent infection; raised CSF protein; abnormal nerve conduction studies
Hyperthyroidism
Thyrotoxic features; abnormal thyroid function tests
Inflammatory myopathy
Elevated creatine kinase; EMG findings
Intoxication (e.g., alcohol, drugs, carbon monoxide)
History of exposure; CNS features; elevated serum drug levels
Myasthenia gravis
Fatigable muscle weakness with positive response to edrophonium; acetylcholine receptor antibodies; decrease in muscle action potentials with repetitive stimulation
Organophosphate poisoning
History of exposure; prominent cholinergic features (e.g., rhinorrhea, excess salivation, bronchospasm) before onset of paralysis
Paralytic shellfish poisoning
History of shellfish ingestion; rapid disease onset; sensory findings
Poliomyelitis
Travel to endemic region; antecedent febrile illness; asymmetric weakness; CSF pleocytosis and elevated protein
Psychiatric conversion disorder
Normal EMG; atypical or inconsistent neurologic signs
Stroke
Asymmetric weakness and upper motor neuron signs; abnormal brain imaging
Tick paralysis
Resident or traveler to endemic areas; ascending paralysis often with paresthesia; tick attached to skin; abnormal nerve conduction
CNS, Central nervous system; CSF, cerebrospinal fluid; EEG, electroencephalogram; EMG, electromyography.
is the mouse lethality bioassay, in which mice are observed for the presence of botulism-specific symptoms after intraperitoneal injection of extracts of clinical specimens. However, sensitivity and specificity are not optimal: in one recent series of injecting drug users fulfilling a strict clinical diagnosis of wound botulism, the mouse bioassay was positive in only 68%.15 Because it is performed in a limited number of laboratories and results may not be available for up to 4 days, it cannot be used as a basis for clinical management decisions. Several rapid in vitro assays that take advantage of the unique endopeptidase activity of each
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neurotoxin subtype have recently been developed and are currently undergoing clinical evaluation. The Endopep-MS assay that uses mass spectrometry to detect peptides cleaved by botulinum toxin reportedly has comparable sensitivity to the mouse lethality bioassay and is completed within 8 hours.16 Presumptive diagnosis of botulism can also be made by testing food or gastric contents for the toxin genes by polymerase chain reaction (PCR) and is more sensitive and rapid than conventional systems.
TREATMENT The core principles of botulism management are the early administration of antitoxin and the prompt recognition of respiratory compromise, allowing the timely implementation of ventilatory support. Having been as high as 70%, the current mortality rate from botulism is less than 5% when adequate intensive care is available. Most antitoxin preparations contain combinations of equinederived antibodies directed against specific botulinum toxin serotypes. A heptavalent botulinum antitoxin (H-BAT) that contains equine-derived antibody to the seven known botulinum toxin types (A–G) was introduced in the United States in 2010. Rather than intact immunoglobulin, H-BAT is predominantly composed of Fab and F(ab’)2 immunoglobulin fragments.17 Removal of the equine Fc fragments significantly reduces the risk of anaphylaxis and serum sickness that complicated use of earlier formulations of antitoxin. F(ab’)2 fragments derived from sheep plasma that have reportedly an even lower risk of toxicity have also been used in the UK and Southeast Asia. The only antitoxin preparation for which there is prospective comparative trial-based evidence of effectiveness is the use of human-derived botulinum immune globulin for the treatment of infant botulism.3 An alternative approach to producing well-tolerated botulinum antitoxin currently in development is germline humanization of antibodies derived from humans or non-human primates.18 Systemic administration of antitoxin neutralizes botulinum toxin that is not yet bound to nerve terminals and thus arrests further disease progression. In a retrospective series of food-borne botulism, its early use is associated with a reduction in mortality and shortening of the duration of respiratory failure requiring ventilatory support. The use of Fab fragments allows the antiserum to reach the extravascular space more effectively and rapidly than whole antibodies. The use of antitoxin is indicated on the basis of clinical suspicion of botulism, and treatment should not be delayed while waiting for the results of laboratory investigations. Botulinum antitoxins are generally given by slow intravenous infusion. Vital signs should be monitored carefully during administration, and medication for the management of acute allergic reactions should be readily available. Some national guidelines recommend repeat treatment within 24 hours if the patient continues to deteriorate. All patients with botulism should be managed in a highdependency setting to facilitate close monitoring. Ventilatory support should be promptly instituted upon development of respiratory compromise, indicated by diminishing vital capacity; up to 50% of patients with food-borne botulism require ventilatory support. Meticulous attention should be paid to the prevention and early treatment of nosocomial infection and to the maintenance of adequate nutritional status. Attendants should remember that, unlike many patients on ventilatory support, patients with botulism are fully awake and have no sensory deficits, unless they have specifically received sedation. In wound botulism, appropriate management of the wound is also essential in order to prevent relapse due to ongoing toxin production by persisting vegetative organisms after antitoxin has been cleared from the body. All wounds should be surgically debrided and treated with antibiotics until completely healed. Relevant wounds may appear trivial or innocuous, and the presence of deep-seated abscesses should be always considered.
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Upon suspicion of a diagnosis of botulism the local public health authorities should be contacted immediately. Investigations should be undertaken to rapidly identify other possible cases and suspected food exposures, as rapid control measures such as impounding home-canned foods or emergency product recalls may need to be instigated. There is currently no licensed prophylactic vaccine against botulism. A pentavalent botulinum toxoid vaccine previously used by the U.S. military was withdrawn in 2011 after the observation of declining immunogenicity. A recombinant bivalent vaccine against subtypes A and B entered phase II studies several years ago, but further development is awaited.19
PEDIATRIC CONSIDERATIONS Clinical Features Constipation is usually the first manifestation of infant botulism. Over 1 to 2 weeks neurologic features develop, leading to presentations with a weakened cry, diminished feeding, and an increasingly “floppy” infant as descending paresis occurs. Examination reveals hypotonia, loss of facial expression, extraocular muscle weakness, and dilated pupils. The extent and severity of clinical features is highly variable, ranging from mild hypotonia to severe flaccid paralysis. Up to 70% of patients require intubation and ventilation, although mortality rates are <1%.
Treatment Historically, equine-derived antitoxin has not been used to treat infant botulism because of concerns regarding serious hypersensitivity reactions and an inadequate duration of therapeutic effect. A human-derived antitoxin product, known as BabyBIG, has been recently developed. A randomized controlled trial demonstrated that when administered early in the disease course, it significantly reduces the duration of mechanical ventilation and length of hospital stay.3 Acknowledgments We thank Dr. Tim Brooks of the Public Health England Rare and Imported Pathogens Laboratory for useful comments and insight during the revision of this manuscript.
REFERENCES
1. Sobel J. Botulism. Clin Infect Dis 2005;41:1167–73. 2. Centers for Disease Control and Prevention. Botulism in the United States, 1899-1996. Atlanta, GA: Handbook for Epidemiologists,
Clinicians, and Laboratory Workers; Centers for Disease Control and Prevention, 1998. 3. Chalk C, Benstead TJ, Keezer M. Medical treatment for botulism. Cochrane Database Syst Rev 2014;(2):CD008123. 4. Reller ME, Douce RW, Maslanka SE, et al. Wound botulism acquired in the Amazonian rain forest of Ecuador. Am J Trop Med Hyg 2006;74(4):628–31. 5. Viray MA, Wamala J, Fagan R, et al. Outbreak of type A foodborne botulism at a boarding school, Uganda, 2008. Epidemiol Infect 2014;142:2297–301. 6. Juliao PC, Maslanka S, Dykes J, et al. National outbreak of type a foodborne botulism associated with a widely distributed commercially canned hot dog chili sauce. Clin Infect Dis 2013;56:376–82. 7. Sobel J, Tucker N, Sulka A, et al. Food-borne botulism in the United States, 1990-2000. Emerg Infect Dis 2004;10:1606–11. 8. Vugia DJ, Mase SR, Cole B, et al. Botulism from drinking pruno. Emerg Infect Dis 2009;15:69–71. 9. Leclair D, Fung J, Isaac-Renton JL, et al. Foodborne botulism in Canada, 1985-2005. Emerg Infect Dis 2013;19:961–8. 10. Werner SB, Passaro D, McGee J, et al. Wound botulism in California, 1951-1998: recent epidemic in heroin injectors. Clin Infect Dis 2000;31:1018–24. 11. Rosow LK, Strober JB. Infant botulism: review and clinical update. Pediatric Neurol 2015;52:487–92. 12. Dabritz HA, Hill KK, Barash JR, et al. Molecular epidemiology of infant botulism in California and elsewhere, 1976-2010. J Infect Dis 2014;210:1711–22. 13. Sheppard YD, Middleton D, Whitfield Y, et al. Intestinal toxemia botulism in 3 adults, Ontario, Canada, 2006-2008. Emerg Infect Dis 2012;18:1–6. 14. Gottlieb SL, Kretsinger K, Tarkhashvili N, et al. Long-term outcomes of 217 botulism cases in the Republic of Georgia. Clin Infect Dis 2007;45:174–80. 15. Wheeler C, Inami G, Mohle-Boetani J, Vugia D. Sensitivity of mouse bioassay in clinical wound botulism. Clin Infect Dis 2009;48:1669–73. 16. Rosen O, Feldberg L, Gura S, et al. Early, Real-time medical diagnosis of botulism by endopeptidase-mass spectrometry. Clin Infect Dis 2015;61:e58–61. 17. Investigational heptavalent botulinum antitoxin (HBAT) to replace licensed botulinum antitoxin AB and investigational botulinum antitoxin E. MMWR Morb Mortal Weekly Rep 2010;59:299. 18. Miethe S, Mazuet C, Liu Y, et al. Development of germline-humanized antibodies neutralizing botulinum neurotoxin A and B. PLoS ONE 2016;11:e0161446. 19. Webb RP, Smith LA. What next for botulism vaccine development? Expert Rev Vaccines 2013;12:481–92.
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Botulism Stephen J. Aston, Nicholas J. Beeching
KEY FEATURES • Rare neuroparalytic illness caused by potent neurotoxins produced by Clostridium botulinum. • Typically presents with bilateral cranial nerve palsies followed by symmetric descending flaccid paralysis and occasional progression to respiratory muscle weakness. • Clostridial spores are ubiquitous in the environment, and botulism is presumed to occur worldwide but under-reporting is significant. • Several naturally occurring forms are recognized: food-borne botulism, wound botulism, infant botulism, and adult intestinal toxemia botulism. • Food-borne disease remains a significant problem in countries where home preservation of food is popular. • Wound botulism has increased in recent years due to an epidemic among people who inject drugs. • Early administration of antitoxin and the prompt recognition of respiratory compromise, allowing the timely implementation of ventilatory support, are key to optimizing outcome.
that produce neurotoxin. After absorption and hematogenous dissemination, botulinum toxin exerts its effects at the presynaptic terminals of cholinergic nerve junctions by blocking neurotransmitter release. Several naturally occurring forms of human botulism are recognized: food-borne botulism, wound botulism, infant botulism, and adult intestinal toxemia botulism. Iatrogenic botulism has been reported after the direct inoculation of concentrated botulinum toxin preparations for cosmetic purposes. Intoxication after absorption of toxin across the respiratory mucosa, termed inhalational botulism, is also recognized.
EPIDEMIOLOGY Attempts to describe the global epidemiology of botulism are hampered by the lack of detailed incidence data. The necessary public health infrastructure to detect and report cases is lacking in many countries, and few case reports have been published.4 In particular, there is a near-complete absence of data from subSaharan Africa.5 Because C. botulinum spores are ubiquitous in the environment, it is presumed that cases occur globally, although rates may vary with dietary customs and food handling practices.
Food-Borne Botulism INTRODUCTION Botulism is a rare, naturally occurring, neuroparalytic illness caused by potent neurotoxins produced by Clostridium botulinum and, rarely, other Clostridium species. It manifests as a characteristic syndrome of symmetric cranial nerve palsies followed to a varying extent by symmetric descending paralysis of voluntary muscle that can progress to respiratory compromise and death. Botulinum spores are ubiquitous in the natural environment, and cases occur worldwide, although are probably greatly under-reported. The first complete clinical description of botulism was published by Kerner in 1822, who termed the disease sausage poisoning, having observed outbreaks associated with the consumption of spoiled meat. The early 20th century saw a massive rise in cases of botulism due to the increasing popularity of food canning, particularly home-made preparations in sealed glass jars. After the elucidation of its mechanism of action in the mid-20th century, the potential therapeutic use of botulinum toxin has been exploited.1–3
Food-borne botulism is caused by consumption of food contaminated with pre-formed botulinum toxin. It is usually associated with uncooked food products, as heating food to >85°C for more than 5 minutes inactivates toxin. Although botulinum spores may potentially contaminate many foodstuffs, germination and toxin production only occur when spores are incubated in an anaerobic, low-salt milieu at greater than 4°C. The processes of canning and fermentation of foods are particularly conducive to producing such conditions. Although effective methods of inactivating spores were introduced in the early 20th century, outbreaks of food-borne botulism attributable to commercially canned foods still account for a substantial proportion of cases in Eastern Europe, and a recent outbreak has been reported in the United States.6 Homecanned foods remain a major source of intoxication, and food-borne botulism occurs with high incidence in areas where home preservation of food is popular, such as Eastern Europe and the Southern United States.7 Several outbreaks in prisons due to illicit alcoholic brew containing fermented vegetables have recently been reported.8 There is an exceptionally high incidence of food-borne botulism in Alaska and some areas of Canada attributable to the consumption of fermented aquatic mammal meat.9
NATURAL HISTORY, PATHOGENESIS, AND PATHOLOGY
Wound Botulism
C. botulinum are anaerobic, gram-positive, spore-forming bacilli that are found in soils and aquatic sediments. Strains of C. botulinum are classified into seven types, designated A to G, according to the antigenic properties of the botulinum toxin they produce. Human botulism is caused by types A, B, E, and rarely type F. Some strains of C. baratii and C. butyricum can also produce botulinum neurotoxin and have been implicated in human disease. The spores of C. botulinum are highly resistant. Under appropriate conditions, they germinate to release vegetative organisms
Wound botulism follows the absorption of toxin produced by organisms contaminating a wound site, so clinical incubation periods are longer than for botulism caused by food, which contains pre-formed toxin. Cases have increased in developed countries in recent years, driven by an epidemic among injecting drug users and strongly associated with the practice of injecting into the subcutaneous tissues or muscle, known as skin or muscle popping.10 Sporadic cases of botulism associated with contaminated compound fractures are occasionally reported.
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Infant Botulism Infant botulism is caused by the endogenous production of toxin by C. botulinum that has colonized the infant gastrointestinal tract after the germination of ingested spores.11 Since its first description in 1976, infant botulism has been reported in all continents except Africa. Globally, most reported cases occur in the United States, where between 1976 and 2010, 2803 cases were reported.12 Ingestion of honey, which is often contaminated by C. botulinum spores, was implicated in some cases, but in the majority a definitive source of botulinum spores was not identified. Recently, contaminated corn syrups have also been implicated, but again with no cases definitively attributed to this exposure. In the absence of a definitive source, acquisition is presumed to occur via ingestion of spores adherent to dust particles.
Adult Intestinal Toxemia Botulism Botulism in adults resulting from in vivo toxin production by Clostridia colonizing the gastrointestinal tract was first demonstrated in the 1980s. In the few cases described, there is often a preceding history of gastrointestinal surgery, inflammatory bowel disease, or antimicrobial use that presumably disrupts the normal microbial flora, allowing colonization by Clostridia species.13
CLINICAL FEATURES The clinical presentation of all forms of botulism is dominated by neurologic features resulting from the toxin-induced blockade of voluntary motor and autonomic cholinergic junctions. Symptoms usually appear between 1 and 5 days after ingestion of the toxin, although very high doses may present within a few hours and progress almost immediately to respiratory paralysis. In adults, cranial nerve palsies are almost always the initial presenting symptoms. Extraocular muscle paresis results in blurred or double vision. Marked ptosis is usually evident, and pupillary responses may also be depressed. The face may appear expressionless as a consequence of bilateral facial nerve dysfunction. Involvement of lower cranial nerves causes dysphonia, dysarthria, and dysphagia. Early autonomic involvement causes anhidrosis, leading affected individuals to complain of extremely dry and often painful, mouth, tongue, and throat. Disease progression manifests as a symmetric, flaccid, descending paralysis of voluntary muscles associated with loss of deep tendon reflexes. Involvement of the diaphragm and accessory thoracic muscles may result in respiratory compromise and death unless supportive care is provided. Due to the generalized lack of motor function, respiratory failure often occurs without apparent features of respiratory distress and may be overlooked until very advanced. Significant pharyngeal muscle weakness causing airway compromise may necessitate intubation and ventilation even in the absence of respiratory muscle weakness. Progressive autonomic involvement leads to constipation, urinary retention, and hemodynamic dysregulation. Fever is usually absent, except in some cases of wound botulism, when it probably indicates concurrent wound infection with other bacteria. Sensory nerves are unaffected by botulinum toxin. Similarly, there is no effect on level of consciousness or cognitive function, although the features of expressionless facies and dysarthria are often mistaken for alcohol or drug intoxication. The extent, severity, and rate of progression of clinical features vary, and not all untreated cases progress to respiratory muscle paralysis. Some affected individuals only develop cranial nerve palsies that gradually resolve without any other features of botulism becoming evident. Botulinum toxin binding is irreversible, and recovery of function depends on nerve terminal regeneration. Individuals with respiratory compromise typically require ventilatory support for 2 to 8 weeks, although occasionally recovery is
much more protracted. Fatigue and generalized weakness may persist for many months after recovery, particularly in older patients and those who have been mechanically ventilated.14 In food-borne disease, the neurologic features of botulism may be preceded by abdominal pain, nausea, vomiting, and diarrhea. Such gastrointestinal disturbance has not been reported in wound botulism and probably represents the effect of other bacteria and their toxins co-contaminating the causative improperly preserved food. Clinical effects of botulinum toxin usually become evident 18 to 36 hours after consumption of the implicated foodstuff.
PATIENT EVALUATION, DIAGNOSIS, AND DIFFERENTIAL DIAGNOSIS In the context of a large outbreak, in which multiple patients present with combinations of cranial nerve palsies and subsequent development of descending flaccid paralysis, botulism is easily recognizable. However, it is a rare condition, and the majority of cases occur singularly, meaning that the diagnosis is often delayed or missed altogether. Botulism should be suspected in any adult with acute-onset gastrointestinal, autonomic, and cranial nerve dysfunction. The four “Ds” are the key clues: dysphonia, dysphagia, dysarthria, and descending paralysis. Demonstration of bilateral cranial nerve findings and evidence of neurologic progression increase the level of suspicion. Reported recent consumption of home canned foods or similar illness in family members or close contacts provides further supporting evidence for the diagnosis. Alternatively, features of injecting drug use are highly suggestive. Important differential diagnoses to consider when botulism is suspected include alcohol or drug misuse, Guillain–Barré syndrome (GBS), myasthenia gravis, stroke syndromes, Eaton–Lambert syndrome, and tick paralysis. Table 60.1 includes other differential diagnoses with important distinguishing features. GBS typically presents as an ascending paralysis, and there is often a history of antecedent infection, typically Campylobacter jejuni gastroenteritis. Distinguishing botulism from the triad of ophthalmoplegia, ataxia, and areflexia that characterizes the Miller–Fisher variant is often more difficult. However, in contrast to botulism, areflexia typically precedes the onset of significant muscle weakness in GBS. Fatigable muscle weakness is the hallmark of myasthenia gravis. A marked improvement with administration of edrophonium is highly suggestive of myasthenia gravis, although about 25% of patients with botulism show some response. Patients with Eaton–Lambert syndrome usually have clinically apparent lung cancer, although electromyographic findings are indistinguishable from botulism. The asymmetric weakness and upper motor neuron signs caused by most stroke syndromes should be readily distinguishable from botulism on clinical examination. Tick paralysis causes paresthesia and ascending paralysis; the diagnosis is particularly apparent if the tick is still attached. Cerebrospinal fluid analysis may be useful; protein levels are normal in botulism, compared with GBS where they are typically raised, although this may not be apparent until several days after symptom onset. Electromyography (EMG) may also be helpful. In particular, repetitive stimulation at high frequencies shows facilitation of muscle action potentials in botulism that is not evident in either GBS or myasthenia gravis. EMG is best performed and interpreted by an experienced operator, because results may vary among muscle groups. To avoid false-negative results, it is essential that clinically affected muscle groups are tested. Brain imaging by computed tomography (CT) or magnetic resonance imaging (MRI) should be used to uncover the rare brainstem stroke syndromes that produce symmetric bulbar palsies. Definitive laboratory confirmation of botulism requires the demonstration of toxin in specimens of patient serum, gastric secretions or stool or, in the case of food-borne botulism, a food sample. The standard method for determining botulinum toxin
CHAPTER 60 Botulism
TABLE 60.1 Differential Diagnoses (In Alphabetical Order) Differential Diagnosis
Distinguishing Features
CNS infections
Altered mental status; abnormal CSF; EEG changes
CNS space-occupying lesion
Asymmetric weakness and upper motor neuron signs; abnormal brain imaging
Diabetic neuropathy
Sensory features; limited cranial nerve involvement
Diphtheria
Antecedent pharyngitis; sensory features; associated cardiac complications
Eaton–Lambert syndrome
Similar EMG findings; often evidence of underlying lung cancer
Electrolyte disturbances (e.g., hypermagnesemia)
Abnormal serum electrolytes
Guillain–Barré syndrome
Ascending paralysis with early areflexia; history of antecedent infection; raised CSF protein; abnormal nerve conduction studies
Hyperthyroidism
Thyrotoxic features; abnormal thyroid function tests
Inflammatory myopathy
Elevated creatine kinase; EMG findings
Intoxication (e.g., alcohol, drugs, carbon monoxide)
History of exposure; CNS features; elevated serum drug levels
Myasthenia gravis
Fatigable muscle weakness with positive response to edrophonium; acetylcholine receptor antibodies; decrease in muscle action potentials with repetitive stimulation
Organophosphate poisoning
History of exposure; prominent cholinergic features (e.g., rhinorrhea, excess salivation, bronchospasm) before onset of paralysis
Paralytic shellfish poisoning
History of shellfish ingestion; rapid disease onset; sensory findings
Poliomyelitis
Travel to endemic region; antecedent febrile illness; asymmetric weakness; CSF pleocytosis and elevated protein
Psychiatric conversion disorder
Normal EMG; atypical or inconsistent neurologic signs
Stroke
Asymmetric weakness and upper motor neuron signs; abnormal brain imaging
Tick paralysis
Resident or traveler to endemic areas; ascending paralysis often with paresthesia; tick attached to skin; abnormal nerve conduction
CNS, Central nervous system; CSF, cerebrospinal fluid; EEG, electroencephalogram; EMG, electromyography.
is the mouse lethality bioassay, in which mice are observed for the presence of botulism-specific symptoms after intraperitoneal injection of extracts of clinical specimens. However, sensitivity and specificity are not optimal: in one recent series of injecting drug users fulfilling a strict clinical diagnosis of wound botulism, the mouse bioassay was positive in only 68%.15 Because it is performed in a limited number of laboratories and results may not be available for up to 4 days, it cannot be used as a basis for clinical management decisions. Several rapid in vitro assays that take advantage of the unique endopeptidase activity of each
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neurotoxin subtype have recently been developed and are currently undergoing clinical evaluation. The Endopep-MS assay that uses mass spectrometry to detect peptides cleaved by botulinum toxin reportedly has comparable sensitivity to the mouse lethality bioassay and is completed within 8 hours.16 Presumptive diagnosis of botulism can also be made by testing food or gastric contents for the toxin genes by polymerase chain reaction (PCR) and is more sensitive and rapid than conventional systems.
TREATMENT The core principles of botulism management are the early administration of antitoxin and the prompt recognition of respiratory compromise, allowing the timely implementation of ventilatory support. Having been as high as 70%, the current mortality rate from botulism is less than 5% when adequate intensive care is available. Most antitoxin preparations contain combinations of equinederived antibodies directed against specific botulinum toxin serotypes. A heptavalent botulinum antitoxin (H-BAT) that contains equine-derived antibody to the seven known botulinum toxin types (A–G) was introduced in the United States in 2010. Rather than intact immunoglobulin, H-BAT is predominantly composed of Fab and F(ab’)2 immunoglobulin fragments.17 Removal of the equine Fc fragments significantly reduces the risk of anaphylaxis and serum sickness that complicated use of earlier formulations of antitoxin. F(ab’)2 fragments derived from sheep plasma that have reportedly an even lower risk of toxicity have also been used in the UK and Southeast Asia. The only antitoxin preparation for which there is prospective comparative trial-based evidence of effectiveness is the use of human-derived botulinum immune globulin for the treatment of infant botulism.3 An alternative approach to producing well-tolerated botulinum antitoxin currently in development is germline humanization of antibodies derived from humans or non-human primates.18 Systemic administration of antitoxin neutralizes botulinum toxin that is not yet bound to nerve terminals and thus arrests further disease progression. In a retrospective series of food-borne botulism, its early use is associated with a reduction in mortality and shortening of the duration of respiratory failure requiring ventilatory support. The use of Fab fragments allows the antiserum to reach the extravascular space more effectively and rapidly than whole antibodies. The use of antitoxin is indicated on the basis of clinical suspicion of botulism, and treatment should not be delayed while waiting for the results of laboratory investigations. Botulinum antitoxins are generally given by slow intravenous infusion. Vital signs should be monitored carefully during administration, and medication for the management of acute allergic reactions should be readily available. Some national guidelines recommend repeat treatment within 24 hours if the patient continues to deteriorate. All patients with botulism should be managed in a highdependency setting to facilitate close monitoring. Ventilatory support should be promptly instituted upon development of respiratory compromise, indicated by diminishing vital capacity; up to 50% of patients with food-borne botulism require ventilatory support. Meticulous attention should be paid to the prevention and early treatment of nosocomial infection and to the maintenance of adequate nutritional status. Attendants should remember that, unlike many patients on ventilatory support, patients with botulism are fully awake and have no sensory deficits, unless they have specifically received sedation. In wound botulism, appropriate management of the wound is also essential in order to prevent relapse due to ongoing toxin production by persisting vegetative organisms after antitoxin has been cleared from the body. All wounds should be surgically debrided and treated with antibiotics until completely healed. Relevant wounds may appear trivial or innocuous, and the presence of deep-seated abscesses should be always considered.
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Upon suspicion of a diagnosis of botulism the local public health authorities should be contacted immediately. Investigations should be undertaken to rapidly identify other possible cases and suspected food exposures, as rapid control measures such as impounding home-canned foods or emergency product recalls may need to be instigated. There is currently no licensed prophylactic vaccine against botulism. A pentavalent botulinum toxoid vaccine previously used by the U.S. military was withdrawn in 2011 after the observation of declining immunogenicity. A recombinant bivalent vaccine against subtypes A and B entered phase II studies several years ago, but further development is awaited.19
PEDIATRIC CONSIDERATIONS Clinical Features Constipation is usually the first manifestation of infant botulism. Over 1 to 2 weeks neurologic features develop, leading to presentations with a weakened cry, diminished feeding, and an increasingly “floppy” infant as descending paresis occurs. Examination reveals hypotonia, loss of facial expression, extraocular muscle weakness, and dilated pupils. The extent and severity of clinical features is highly variable, ranging from mild hypotonia to severe flaccid paralysis. Up to 70% of patients require intubation and ventilation, although mortality rates are <1%.
Treatment Historically, equine-derived antitoxin has not been used to treat infant botulism because of concerns regarding serious hypersensitivity reactions and an inadequate duration of therapeutic effect. A human-derived antitoxin product, known as BabyBIG, has been recently developed. A randomized controlled trial demonstrated that when administered early in the disease course, it significantly reduces the duration of mechanical ventilation and length of hospital stay.3 Acknowledgments We thank Dr. Tim Brooks of the Public Health England Rare and Imported Pathogens Laboratory for useful comments and insight during the revision of this manuscript.
REFERENCES
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