Chapter 11 Botulism

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Botulism is an acute neuroparalytic disease of humans and animals caused through the action of botulinum neurotoxins (BoNTs) acting at the neuromuscular junction (NMJ) of somatic nerves that innervate cranial and skeletal muscle. This results in the blockade of release of acetylcholine (ACh) with ensuing denervation and accompanying muscle paralysis and atrophy. Botulism is a presynaptic myasthenic neuromuscular syndrome exhibiting muscle weakness as its primary clinical sign. BoNTs are produced by heterogeneous group of clostridial bacteria that differ widely in genetic and metabolic characteristics. BoNTs are the most potent protein toxins and their toxicity depends on the route of entry into the human body. The diagnosis of botulism relies on the clinical findings that include prominent oculo-bulbar signs and laboratory detection of BoNT from appropriate specimens. The mainstay of treatment is intensive nursing care, with careful attention to respiratory failure, need for enteric feeding and cardiac arrest. Recovery from botulism is slow and tedious. The cellular mechanisms of BoNTs of activity were elucidated by new techniques and concepts, particularly advanced techniques for imaging tissue, electrophysiological methods, the theory of quantal release of acetylcholine at the synaptic membrane and genetic analyses, and structural analyses of the BoNTs. The pathophysiology of synaptic and postsynaptic effects from BoNT has been thoroughly studied in animal models. BoNTs affect synaptic activity of central neurons in tissue preparations at high doses or after direct intracranial injection. Motor systems throughout life within an organism have a dynamic capacity for adaptive remodeling and plasticity changes.

Introduction

Botulism is an acute neuroparalytic disease of humans and animals caused through the action of botulinum neurotoxins (BoNTs) primarily acting at the neuromuscular junction (NMJ) of somatic nerves that innervate cranial and skeletal muscle. This results in the blockade of release of acetylcholine (ACh) with ensuing denervation and accompanying muscle paralysis and atrophy. BoNT also blocks neurotransmission at cholinergic parasympathetic and postganglionic sympathetic nerves, affecting smooth muscle activity and glandular and secretory functions and impairing certain autonomic activities. Botulism generally presents with symptoms of fatigability affecting bulbar and ocular musculature and, in severe cases, weakness of the neck, limbs, torso and ensuing generalized paralysis. Botulism can be life‐threatening, generally due to respiratory paralysis and failure and occasionally due to secondary infections or cardiac arrest. Although botulism is considered an acute intoxication, the duration of paralysis can last for weeks to months and complete recovery requires restoration of neurotransmission and muscle function. During the past century, death caused by botulism has decreased from ca. 70% to ca. 10% worldwide due primarily to clinical recognition of the disease, prompt administration of antitoxin, intensive nursing care, mechanical ventilation, parenteral feeding and control of secondary infections. Botulism outbreaks have had dramatic and devastating impacts on human and animal populations in which they occur (Meyer 1956, Dolman 1964).

Botulism is a true toxemia, caused solely through the action of BoNT at cholinergic nerve terminals. BoNTs are protein toxins of 150 kDa produced by neurotoxigenic bacteria of the genus Clostridium. Seven serotypes (A, B, C, D, E, F and G) are currently distinguished (Sugiyama 1980, Sakaguchi 1983, DasGupta 1989, Schiavo 2000). BoNTs are the most poisonous substances known and, currently, there is no antidote to botulism other than passive administration of antitoxin within hours after toxin exposure or immunization of at‐risk individuals prior to exposure (Arnon et al., 2005). Since botulism is an extremely rare disease, general immunization of human populations is not practical and would prevent the pharmaceutical use of BoNT for treatment of human disease (Johnson, 1999).

Six clinical forms of botulism are recognized (Hatheway 1995, Centers for Disease Control and Prevention (CDC) 1998, Cherington 2004): 1. classic foodborne botulism; 2. wound botulism; 3. intestinal botulism including infant botulism; 4. inhalational botulism; 5. botulism of unknown source; and 6. inappropriate administration of botulinum toxin during its use as a pharmaceutical agent (iatrogenic botulism). Intentional botulism poisoning by oral or inhalation exposure such as in a bioterrorist event could be considered as a seventh class with potentially severe consequences (Hatheway 1994, Caya 2004). Foodborne botulism through ingestion of BoNT by the oral route is the most prevalent natural form of botulism that occurs worldwide. However, currently the most common route of exposure of humans to BoNTs is by injection for medicinal treatment of a variety of neurological disorders and therapeutic uses, a remarkable development of this toxin (Scott 1989, Schantz 1992, Jankovic 1994, Johnson 1999, Moore 2003). A very large number of injections are performed each year in humans and the disease syndromes being treated continue to expand at a rapid rate.

The primary objective of this chapter is to address the pathophysiology of botulism with emphasis on the basic science governing the clinical effects, diagnosis, treatment and recovery. Recent aspects regarding epidemiology, pathophysiology and molecular mechanisms of BoNTs are briefly described. Several excellent and in‐depth reviews on the biochemistry, structure and pharmacology of BoNT are available (Schiavo 2000, Brin 2002, Moore 2003, Jahn 2006) and the reader is referred to these treatises for in‐depth descriptions of these subjects.

Section snippets

Brief history of botulism as a neuromuscular disorder

Botulism is a presynaptic myasthenic neuromuscular syndrome exhibiting muscle weakness as its primary clinical sign. As such, it shares similarities with other myasthenic syndromes such as myasthenia gravis and Lambert–Eaton syndrome as well as a number of other congenital and acquired diseases and chemical and biological intoxications (Kaminski, 2003; Meriggioli et al., 2005; Holmes et al., 2006). Botulism likely occurred as a dreaded food poisoning in ancient cultures, including the 10th

Sources of botulinum neurotoxins

Botulinum neurotoxins are produced by a heterogeneous group of clostridial bacteria that differ widely in genetic and metabolic characteristics (Popoff 1995, Hatheway 1998, Franciosa 2003, Johnson 2007). The exceptional feature of neurotoxigenic clostridia is their formation of a characteristic neurotoxin of extraordinary potency for humans and certain animals (botulinum and tetanus neurotoxins) (Sugiyama 1980, Sakaguchi 1983, Schiavo 2000). Other key features of the neurotoxigenic clostridia

Toxicity and antitoxins

BoNTs are the most potent protein toxins known and their toxicity depends on the route of entry into the human body. They can enter the blood through the intestine, wounds and mucosal membranes. The estimated intravenous and intramuscular human lethal doses of BoNTs are 0.1–1 ng per kg body weight (Gill 1982, Schantz 1992, Hatheway 1994), whilst more than a one thousand times lower toxicity is detected using the oral route (Morton 1961, Hatheway 1994; Larson and Johnson, unpublished review

General properties of botulinum neurotoxin

Biochemical and structural investigations of BoNT and TeNT and their domains have provided considerable insight into their evolution and mode of action (DasGupta 1989, Schiavo 2000, Hanson 2002, Swaminathan 2002). BoNTs are synthesized as inactive single chain molecules of 150 kDa, that assume their characteristic high toxicity by proteolytic activation into a ca. 100 kDa heavy chain (HC) and a ca. 50 kDa light chain (LC) that remain linked by a single disulfide bond (DasGupta 1989, Schiavo 2000

Types of botulism

The primary target of BoNTs is the NMJ of the peripheral nervous system and BoNT also binds to preganglionic sympathetic and parasympathetic nerve endings, postganglionic parasympathetic nerve endings and efferent motor nerve endings (Simpson, 2000). Botulism is a blood‐borne toxicosis and the susceptibility of animals to different serotypes varies considerably across species. In humans, the primary serotypes of BoNT responsible for botulism are A, B, E and, rarely, F. The different forms of

Clinical presentation

Irrespective of the type of botulism, the primary clinical signs are similar:

  • Symmetrical cranial neuropathies;

  • Difficulty swallowing, dry mouth, difficulty speaking, facial ptosis;

  • Blurred near vision, blurred distant vision, dilated or non‐reactive pupils, diplopia, drooping eyelids;

  • Descending bilateral flaccid paralysis, generalized muscle weakness progressing to neck, limbs and torso.

The characteristic symptoms of botulism can principally be ascribed to the blockade of neurotransmission at

Diagnosis of botulism

The diagnosis of botulism relies on the clinical findings which include prominent oculobulbar signs and laboratory detection of BoNT from appropriate specimens (Table 11.2) (Hughes 1981, Cherington 1998, Cherington 2004, Shapiro 1998, Arnon 2004). The initial diagnosis of botulism is based on the characteristic clinical presentation as described in the previous section (Centers for Disease Control and Prevention (CDC) 1998, Cherington 1998, Cherington 2004).

The definitive laboratory diagnosis

Treatment of botulism

The mainstay of treatment is intensive nursing care, with careful attention to respiratory failure, need for enteric feeding and cardiac arrest (Woodruff 1992, Arnon 2004, Cherington 2004, Centers for Disease Control and Prevention (CDC) 2006). Passive immunization has long been known to lessen the symptoms of botulism and length of clinical course and reduce the incidence of fatalities (Dack 1928, Hatheway 1984, Tacket 1984, Mayers 2001, Chang 2003, Arnon 2006). When administered within hours

Recovery from botulism and clinical predictors of mortality

Recovery from botulism is slow and tedious. A retrospective review of cases in the USA found a mean of 58 days of mechanical ventilation for type A and 26 days for type B (Colice, 1987). Recovery of speech and the ability to swallow recurs relatively early. Muscular weakness, vertigo and constipation diminish more slowly and may persist for several months. The oculobulbar disturbances are usually the last symptoms to clear. Some patients continue to experience weakness, fatigue and symptoms of

Pathophysiology of botulism and cellular mechanisms of botulinum neurotoxins

Animal models and tissue preparations have traditionally been employed to study the pathophysiology of botulism (Drachman 1971, Habermann 1986, Simpson 2000). The specificity and action of BoNTs for different tissues and cell types depends on the receptor systems, the trafficking mechanisms and the isoforms of SNARE proteins present in the cells (Schiavo et al., 2000). In this section of the chapter, molecular and tissue effects are described with an emphasis on new developments. It follows the

Background

The cellular mechanisms of BoNTs of activity remained enigmatic for several decades, began to be revealed in the 1950s and 1960s and were gradually elucidated by new techniques and concepts, particularly advanced techniques for imaging tissue, electrophysiological methods, the theory of quantal release of acetylcholine at the synaptic membrane and eventually genetic analyses and structural analyses of the BoNTs (Heuser 1976, Katz 1966, Thesleff 1976, Niemann 1991, Schiavo 2000). The morphology

Synaptic and postsynaptic effects

The synaptic and postsynaptic pathophysiology of BoNTs and secondary actions on muscle have been much less studied than presynaptic activities at nerve terminals. The onset, duration of paralysis, time for recovery and effects in distal neuromuscular regions is highly dependent on the serotype of BoNT, muscle activity, muscle stimulation and other factors (Hughes 1962, Eleopra 1997, Eleopra 2004, Eleopra 2006, Sloop 1997, Hesse 1998, Davletov 2005). The toxin's efficacy also depends strongly on

Central effects of botulinum neurotoxins

For many years there has been considerable debate about whether physiological concentrations of BoNT can enter the CNS (e.g., Koenig 1971, Boroff 1975, Habermann 1986, de Groot 2002, Abbruzzese 2006). This is an intriguing area of study since BoNT injections have been tried to alleviate CNS‐related syndromes including pain, epilepsy, migraine, visual function and psychological disorders such as depression (Aoki 2003, Benecke 2003, Lang 2003, Luvisetto 2003, Luvisetto 2004, Luvisetto 2006,

Possible role of BoNT in neuronal plasticity and learning

Motor systems throughout life within an organism have a dynamic capacity for adaptive remodeling and plasticity changes (Sanes 2000, Franchi 2002). For several years, certain physicians have reported that treatment of children for cerebral palsy with BoNT sometimes leads to positive adaptation of muscle function over time. Motor cortex reorganization has been proposed to occur following injection of BoNT/A into various muscles (Franchi, 2002). Adaptive changes in motor control have been

Emergency information

The seriousness of botulism led to the establishment of a National Botulism Laboratory at the Centers for Disease Control and Prevention in the United States and similar laboratories in certain other countries. In suspected cases of botulism, the CDC can be contacted at www.cdc.gov and the emergency 24‐hour phone number for state health departments is 770‐4888‐7100. Medical care providers who suspect botulism in patients should immediately call their state health department's emergency 24‐hour

Acknowledgments

EAJ acknowledges support from the Pacific Southwest Regional Center of Excellence (grant U54 AI065359) and the Great Lakes Regional Center of Excellence (U54 AI57153), the University of Wisconsin – Madison, and sponsors of the Food Research Institute; and that in CM's laboratory by a Telethon grant and the Armenise‐HMS Foundation. The authors are grateful to members of their laboratories over the years and to collaborators and mentors on various projects involving neurotoxigenic clostridia and

References (396)

  • JG Colebatch et al.

    Slow recovery from severe foodborne botulism

    Lancet

    (1989)
  • BR DasGupta

    The structure of botulinum neurotoxin

  • BR DasGupta et al.

    Botulinum neurotoxin type A—sequence of amino acids at the N‐terminus and around the nicking site

    Biochimie

    (1990)
  • BR DasGupta et al.

    Purification and amino acid composition of type E botulinum neurotoxin

    Toxicon

    (1983)
  • BR DasGupta et al.

    Purification and amino acid composition of type A botulinum neurotoxin

    Toxicon

    (1984)
  • B Davletov et al.

    Beyond BOTOX: advantages and limitations of individual botulinum neurotoxins

    Trends Neurosci

    (2005)
  • A de Paiva et al.

    A role for interchain disulfide or its participating thiols in the internalization of botulinum neurotoxin A revealed by a toxin derivative that binds to ecto‐acceptors and inhibits transmitter release intracellularly

    J Biol Chem

    (1993)
  • SK Dessain et al.

    High efficiency creation of human monoclonal antibody‐producing hybridomas

    J Immunol Meth

    (2004)
  • M Dezfulian

    Animal models of botulism

  • G Abbruzzese et al.

    Neurophysiological effects of botulinum toxin type A

    Neurotox Res

    (2006)
  • P Abgueguen et al.

    Nine cases of foodborne botulism type B in France and literature review

    Eur J Clin Microbiol Infect Dis

    (2003)
  • CE Adams

    Embryonic mortality induced experimentally in the rabbit

    Nature

    (1960)
  • CR Ahsan et al.

    Visualization of binding and transcytosis of botulinum toxin by human intestinal cells

    J Pharmacol Exp Therapeut

    (2005)
  • Y Aikawa et al.

    A second SNARE role for exocytic SNAP25 in endosome fusion

    Molec Biol Cell

    (2006)
  • K Alderson

    Motor nerve terminal morphology following botulinum A toxin injection in humans

  • CG Andrew et al.

    Susceptibility of skeletal muscle to cosackie A2 virus infection. Effects of botulinum toxin and denervation

    Science

    (1984)
  • B Antharavally et al.

    Status of cys residues in the covalent structure of botulinum neurotoxins A, B, and E

    J Prot Chem

    (1998)
  • KR Aoki

    Botulinum neurotoxin serotypes A and B preparations have different safety margins in preclinical models of muscle weakening efficacy and systemic safety

    Toxicon

    (2002)
  • KR Aoki

    Evidence for antinociceptive activity of botulinum toxin type A in pain management

    Headache

    (2003)
  • JW Arndt et al.

    Structure of botulinum neurotoxin type D light chain at 1.65 ansgstrom resolution: repercussions for VAMP‐2 substrate specificity

    Biochemistry

    (2006)
  • SS Arnon

    Infant botulism

  • SS Arnon et al.

    Infant botulism in 1931—discovery of a misclassified case

    Am J Dis Child

    (1979)
  • SS Arnon et al.

    Infant botulism: epidemiology and relation to sudden infant death syndrome

    Epidemiol Rev

    (1981)
  • SS Arnon et al.

    Botulinum toxin as a biological weapon. Medical and public health management

    JAMA

    (2005)
  • SS Arnon et al.

    Human immune globulin in for the treatment of infant botulism

    N Engl J Med

    (2006)
  • FJ Arntzen et al.

    Fatal type A botulism in South Africa, 2002

    Trans R Soc Trop Med Hyg

    (2004)
  • A Ashkenazi et al.

    Botulinum toxin and other approaches to migraine therapy

    Annu Rev Med

    (2004)
  • AC Ashton et al.

    Characterization of the inhibitory activity of botulinum neurotoxin type A on the release of several transmitters from rat cerebrocortical synaptosomes

    J Neurochem

    (1988)
  • OL Avila et al.

    Neurotransmission regulates stability of acetylcholine receptors at the neuromuscular junction

    J Neurosci

    (1989)
  • SM Bajjalieh et al.

    SV2, a brain synaptic vesicle protein homologous to bacterial transporters

    Science

    (1992)
  • SM Bajjalieh et al.

    Brain contains 2 forms of synaptic vesicle protein‐2

    Proc Natl Acad Sci U S A

    (1993)
  • SM Bajjalieh et al.

    Differential expression of synaptic vesicle protein‐2 (SV2) isoforms

    J Neurosci

    (1994)
  • M Bajohrs et al.

    A molecular basis underlying differences in the toxicity of botulinum serotypes A and E

    EMBO Rep

    (2004)
  • AM Bakheit et al.

    Generalised botulism‐like syndrome after intramuscular injections of botulinum toxin type A: a report of two cases

    J Neurol Neurosurg Psychiatry

    (1997)
  • MR Baldwin et al.

    Association of botulinum neurotoxin serotypes A and B with synaptic vesicle protein complexes

    Biochemistry

    (2007)
  • ML Barclay et al.

    Aminoglycoside toxicity and relation to dose regimen

    Adverse Drug React Toxicol Rev

    (1994)
  • JC Bartlett

    Infant botulism in adults

    N Engl J Med

    (1986)
  • U Bartram et al.

    Infant botulism and sudden infant death syndrome

    Klin Padiatr

    (2004)
  • R Benecke et al.

    Botulinum toxin in the treatment of muscle pain

    Schmerz

    (2003)
  • KP Bhatia et al.

    Generalized muscular weakness after botulinum toxin injections for dystonia: a report of three cases

    J Neurol Neurosurg Psychiatry

    (1999)
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