CHAPTER 50: BOTULISM

Botulism, recognized at least since the eighteenth century, is a neuroparalytic disease caused by botulinum toxin, one of the most toxic substances known. While initially thought to be caused only by the ingestion of botulinum toxin in contaminated food (food-borne botulism), three additional forms caused by in situ toxin production after germination of spores in either a wound or the intestine are now recognized worldwide: wound botulism, infant botulism, and adult intestinal colonization botulism. In addition to occurring in these recognized natural forms of the disease, botulism symptoms have been reported in patients receiving injections of botulinum toxin for cosmetic or therapeutic purposes (iatrogenic botulism). Moreover, botulism was reported after inhalation of botulinum toxin in a laboratory setting. All forms of botulism manifest as a relatively distinct clinical syndrome of symmetric cranial-nerve palsies followed by descending bilateral flaccid paralysis of voluntary muscles, which may progress to respiratory compromise and death. The mainstays of therapy are meticulous intensive care and treatment with antitoxin as soon as botulism is suspected and before other illnesses have been ruled out.

Seven serologically distinct confirmed serotypes of botulinum toxin (A through G) have been confirmed. Botulinum toxin is produced by four recognized species of clostridia: Clostridium botulinum, Clostridium argentinense, Clostridium baratii, and Clostridium butyricum. Certain strains may produce more than one serotype. All are anaerobic gram-positive organisms that form subterminal spores; C. botulinum and C. argentinense spores have been recovered from the environment. The spores survive environmental conditions and ordinary cooking procedures. Toxin production, however, requires a rare confluence of product storage conditions: an anaerobic environment, a pH of >4.6, low salt and sugar concentrations, and temperatures of >4°C. Although commonly ingested, spores do not normally germinate and produce toxin in the adult human intestine.

Food-borne botulism is caused by consumption of foods contaminated with botulinum toxin; no confirmed host-specific factors are involved in the disease. Wound botulism is caused by contamination of wounds with C. botulinum spores, subsequent spore germination, and toxin production in the anaerobic milieu of an abscess or a wound. Infant botulism results from absorption of toxin produced in situ by toxigenic clostridia colonizing the intestine of children ≤1 year of age. Colonization is thought to occur because the normal bowel microbiota is not yet fully established; this theory is supported by studies in animals. Adult intestinal colonization botulism, a very rare form that is poorly understood, has a pathology similar to that of infant botulism but occurs in adults; typically, patients have some anatomic or functional bowel abnormality or have recently used antibiotics that may help toxigenic clostridia compete more successfully against the normal bowel microbiota. Despite antitoxin treatment, relapse due to intermittent intraluminal production of toxin may be observed in patients with adult intestinal colonization botulism.

Regardless of how exposure occurs, botulinum neurotoxin enters the vascular system and is transported to peripheral cholinergic nerve terminals, including neuromuscular junctions, postganglionic parasympathetic nerve endings, and peripheral ganglia. Botulinum toxin is a zinc-endopeptidase protein of ~150 kDa, consisting of a 100-kDa heavy chain and a 50-kDa light chain. Steps in neurotoxin activity include (1) heavy-chain binding to nerve terminals, (2) internalization in endocytic vesicles, (3) translocation of the light chain to cytosol, and (4) light-chain serotype-specific cleavage of one of several proteins involved in the release of the neurotransmitter acetylcholine. Inhibition of acetylcholine release by any of the seven toxin serotypes results in characteristic flaccid paralysis. Recovery follows sprouting of new nerve terminals.

All botulinum toxin serotypes have been demonstrated to cause botulism in nonhuman primates. Human cases associated with serotypes A, B, E, and F are reported each year. Serotype A produces the most severe syndrome, with the greatest proportion of patients requiring mechanical ventilation. Serotype B appears to cause milder disease than type A in both food-borne and infant botulism. Serotype E, most often associated with foods of aquatic origin, produces a syndrome of variable severity. The rare cases of illness caused by toxin serotype F, whether in infants or adults, are characterized by rapid progression to quadriplegia and respiratory failure but also by relatively rapid recovery. Recent studies have shown that at least some serotypes can be differentiated into subtypes through neurotoxin gene sequencing; however, the impact of these subtype differences on clinical illness is not yet known.

Botulism occurs worldwide, but the number of cases reported varies among countries and regions. The variation may be due not only to actual differences in incidence but also to (1) availability of resources to identify botulism, a rare disease; (2) differences in reporting requirements; and (3) limited external access to data collections. There is no universal surveillance system to capture worldwide botulism incidence. However, 30 countries currently participate in voluntary reporting of botulism cases to the European Union through an established surveillance system that includes standardized case definitions similar to those used in the United States and Canada. Other countries (e.g., Argentina, China, Thailand, Japan) maintain independent botulism surveillance.

Food-borne botulism

From 1899 to 2011, 1225 food-borne botulism events (single cases or outbreaks) were reported in the United States; from 1990 to 2000, a median of 23 cases were reported annually. Most such events (~80%) involve vegetables or fish/aquatic animals, usually home-preserved (canned, jarred). Native communities in both the United States (Alaska) and Canada have a high incidence of food-borne botulism due to traditional food-preparation practices; 85% of all cases in Canada occur in Native communities. Outbreaks typically involve two or three cases; however, one restaurant-associated outbreak in 1977 affected 59 persons. Worldwide, the highest incidence rate is reported from Georgia and Armenia in the southern Caucasus region, where illness is also associated with home-canning practices. Outbreaks in Asia are attributable to consumption of home-preserved fish or vegetable products such as bean curd and bamboo shoots. In parts of Europe, including Poland, France, and Germany, illness is often associated with home-preserved meat such as ham or sausage. Since 1950, commercial products have rarely been implicated in botulism in the United States, and botulism from commercial products is most often attributed to consumer error in storage or cooking. However, manufacturer deficiencies do occur. In 2007, botulism developed in eight persons in the United States who consumed a commercially canned hot-dog chili sauce. Significant deficiencies discovered by regulatory authorities involved 91 different products and resulted in the recall of 111 million cans of food.

Wound botulism

This form of disease was first recognized in 1951 as a result of a review of the clinical records on an accidental injury in 1943. Between 1943 and 2011, 491 cases of wound botulism were reported in the United States; 97% of cases reported after 1990 were associated with injection drug use. The typical patient was a 30- to 50-year-old resident of the western United States with a long history of black-tar heroin injection. In the early 2000s, wound botulism associated with drug use emerged in Europe, and at least two case clusters have been reported.

Infant botulism

More than 3900 infant botulism cases have been reported worldwide (84% in the United States alone) since this form of the disease was first recognized in 1976; ~80–100 cases (commonly caused by serotypes A and B) are reported annually in the United States.

Adult intestinal colonization botulism

This form of botulism is difficult to confirm because it is poorly understood and because no clear guidelines are available to help differentiate it from other adult botulism cases. Often these cases are caused by C. baratii type F, but the involvement of both C. botulinum type A and C. butyricum type E has been reported.

Iatrogenic botulism

Paralysis of variable severity has followed injection of licensed botulinum toxin products for treatment of conditions involving hypertonicity of large muscle groups. The U.S. Food and Drug Administration received 658 reports of adverse events related to botulinum toxin use—some very serious—between 1997 and 2006. Although some patients had symptoms consistent with botulism, no cases were laboratory confirmed. Injection of approved doses of licensed products for cosmetic purposes has not been associated with botulism. However, four cases of laboratory-confirmed botulism resulted from illegal injection of research-grade toxin for cosmetic purposes in a U.S. medical facility in 2004.

Inhalational botulism

Inhalational botulism does not occur naturally. One report from Germany has described botulism resulting from possible inhalational exposure to botulinum toxin in a laboratory incident.

Intentional botulism

Botulinum toxin has been “weaponized” by governments and terrorist organizations. An attack might use aerosolization of toxin or contamination of foods or beverages ranging in scope from small-scale tampering to contamination of a widely distributed food item. An unnatural event may be suggested by unusual relationships between patients (e.g., a visit to the same building), atypical exposure vehicles, or atypical toxin serotypes.

The distinctive clinical syndrome of botulism consists of symmetric cranial-nerve palsies followed by bilateral descending flaccid paralysis that may progress to respiratory failure and death. The incubation period from ingestion of contaminated food to onset of symptoms in food-borne botulism is usually 8–36 h but can be as long as 10 days and is dose dependent. Incubation periods of 4–17 days have been documented in wound botulism associated with accidental injury. However, estimation is difficult in cases involving injection drug users because most of these patients inject drugs several times daily. Similarly, the incubation period for infant botulism has not been established, but the fact that the illness has affected infants <3 days old suggests that this interval may be very short.

Cranial nerve deficits may include some of the following: diplopia, dysarthria, dysphonia, ptosis, ophthalmoplegia, facial paralysis, and impaired gag reflex. Pupillary reflexes may be depressed, and fixed or dilated pupils are sometimes noted. Autonomic symptoms such as dizziness, dry mouth, and very dry, occasionally sore throat are common. Constipation due to paralytic ileus is nearly universal, and urinary retention is also common. Patients are afebrile and remain alert and oriented. Respiratory failure may occur due to either paralysis of the diaphragm and accessory breathing muscles or pharyngeal collapse secondary to cranial nerve paralysis. Weakness descends, often rapidly, from the head to involve the neck, arms, thorax, and legs; occasionally, weakness is asymmetric. Deep tendon reflexes may be normal or may progressively disappear. Paresthesias, while rare, have been reported and may represent secondary nerve compression from immobility due to paralysis. Absence of cranial nerve palsies or their onset after the appearance of other true neurologic symptoms makes botulism highly unlikely. Nausea, vomiting, and abdominal pain may precede or follow the onset of paralysis in food-borne botulism. Infants with botulism typically present with reduced ability to suck and swallow, constipation, weakened voice, ptosis, sluggish pupils, hypotonia, and floppy neck; as in adults, illness can progress to generalized flaccidity and respiratory compromise.

Even when intubated, patients can respond to questions by moving their fingers or toes unless paralysis has affected the digits. In some instances, unfortunately, the severe ptosis, expressionless face, and weak phonation of patients with botulism have been interpreted as signs of mental status changes due to alcohol intoxication, drug overdose, encephalitis, or meningitis—a conclusion that delays an accurate diagnosis. Because of skeletal muscle paralysis, patients experiencing respiratory distress may appear placid and detached even as they near respiratory arrest. Death in untreated botulism is usually due to airway obstruction from pharyngeal muscle paralysis and inadequate tidal volume resulting from paralysis of diaphragmatic and accessory respiratory muscles. Death can also result from hospital-associated infections and other sequelae of long-term paralysis, hospitalization, and mechanical ventilation.

A history of preparing home-canned foods may assist with the diagnosis. Patients with wound botulism may or may not have a discernible wound or abscess. A history of injection drug use or the presence of track marks may raise suspicion of the diagnosis. Clinical improvement follows sprouting of new nerve terminals and may take weeks to months. Patients often require outpatient rehabilitation therapy and may experience residual deficits.

Botulism is diagnosed primarily on clinical grounds, with laboratory confirmation by specific tests that identify botulinum toxin in clinical and food samples. In the setting of an outbreak with multiple patients presenting to the same treatment facility, the diagnosis is apparent as long as physicians recognize that cases within a cluster may have varied signs and symptoms. The temporal occurrence of two or more cases with symptoms compatible with botulism is essentially pathognomonic because other illnesses that resemble botulism do not usually occur in clusters. In lone (sporadic) cases, the diagnosis is often missed. The rarity of this disease prevents many physicians from gaining experience with its clinical diagnosis, and some patients present with signs and symptoms that do not fit the classic pattern. Assessing clinical characteristics of other paralytic illnesses in single cases is sometimes critical to rule in or rule out the diagnosis of botulism.

In adults, a food history and the names of contacts who may have shared foods should be obtained before illness progresses to respiratory failure; specific questions should include information about the consumption of home-preserved and/or exotic foods and of products requiring refrigeration that have been left at room temperature in sealed plastic containers or bags. A history of recent consumption of home-canned food substantially enhances the probability of food-borne botulism.

Ascertainment of the patient’s behavioral history related to injection drug use is critical to the diagnosis of wound botulism unless an accidental wound is evident. Caretakers’ observations up to and including the onset of symptoms are vital to the diagnosis of infant botulism. A history of recent abdominal surgery or antibiotic use may be important in the diagnosis of adult intestinal colonization botulism.

Differential diagnosis

The illnesses most commonly considered in the differential diagnosis of adult botulism cases include Guillain-Barré syndrome (GBS), myasthenia gravis, stroke syndromes, Eaton-Lambert syndrome, and tick paralysis. Less likely possibilities are poisoning by tetrodotoxin, shellfish, or a host of rarer agents and antimicrobial drug–associated paralysis. A thorough history and a meticulous physical examination can effectively eliminate most alternative diagnoses, but a workup for other diagnoses should not delay treatment with botulinum antitoxin.

GBS, a rare autoimmune demyelinating polyneuropathy that often follows an acute infection, presents most often as an ascending paralysis. Case clusters are rare. Occasional GBS cases present as the Miller Fisher variant, whose characteristic triad of ophthalmoplegia, ataxia, and areflexia is easily mistaken for the early descending paralysis of botulism. Protein levels in cerebrospinal fluid (CSF) are elevated in GBS; because this increase may be delayed until several days after symptom onset, an early lumbar puncture with a negative result may need to be repeated. In contrast, CSF findings are generally normal in botulism, although marginally elevated CSF protein concentrations have been reported. In experienced hands, electromyography may differentiate GBS from botulism.

The edrophonium (Tensilon) test is sometimes of value in distinguishing botulism (usually a negative result) from myasthenia gravis (usually a positive result).

In most cerebrovascular accidents, physical examination reveals asymmetry of paralysis and upper motor neuron signs. Brain imaging can reveal the rare basilar stroke that produces symmetric bulbar palsies. Eaton-Lambert syndrome usually manifests as proximal limb weakness in a patient already debilitated by cancer. Tick paralysis is a rare flaccid condition closely resembling botulism and caused by neurotoxins of certain ticks.

Botulism-specific laboratory tests

Botulism is confirmed in the laboratory by demonstration of toxin in clinical specimens (e.g., serum, stool, gastric aspirate, and sterile-water enema samples) or in samples of ingested foods. Isolation of toxigenic clostridia from stool also provides evidence of botulism. Wound cultures yielding the organism are highly suggestive in symptomatic cases. The universally accepted method for confirmation of botulism is the mouse bioassay, which is available only in specialized laboratories. Specific guidance about what specimens to collect should be obtained from the testing laboratory because the requirements vary with the form of botulism suspected. Clinical specimens collected early in the hospital admission process should be submitted for testing; toxin results may be negative if specimens are collected >7 days after symptom onset. Because of the extreme potency of botulinum toxin, a test may yield a negative result even when a patient has botulism; thus, a negative result does not exclude this diagnosis. In suspected wound botulism, material from abscesses should be collected in anaerobic culture tubes. New laboratory tests for botulism are being developed but remain experimental. Nerve conduction studies showing reduced amplitude of motor potentials—with or without potentiation by rapid repetitive stimulation in weak muscles—and needle electromyography showing small-motor-unit action potentials are consistent with botulism; these results and those that make alternative diagnoses more likely may be useful. Standard blood work and radiologic studies are not useful in diagnosing botulism.

Every botulism case is a public health emergency. Antitoxin is not universally available. Some countries maintain stockpiles of antitoxin for immediate response, whereas others must access supplies from other nations when an outbreak occurs.

In the United States, clinicians must report every suspected case, regardless of form, on an emergency basis to their state health department. The state health department may put the physician in contact with the 24/7 botulism consultation service at the Centers for Disease Control and Prevention (CDC) through the CDC Emergency Operations Center (770-488-7100) or a locally available service. The botulism consultant will review the case and determine whether botulism is likely. If indicated, the consultant will coordinate laboratory confirmation at appropriate testing facilities and facilitate emergency shipment of antitoxin for all adult cases and for infant cases not involving serotypes A and B. In this country, botulinum antitoxin for noninfant cases is available exclusively from the CDC. Physicians who see suspected infant botulism cases should contact the California Department of Public Health Infant Botulism Treatment and Prevention Program (510-231-7600), which provides 24-h consultation and distributes antitoxin (BabyBIG) for the treatment of infant botulism nationwide. Except in cases involving infants who reside in California, laboratory testing requests must still be authorized by the state health department where the infant is located or by the CDC.

No prophylaxis or licensed vaccine is available against botulism. Home-canning instructions and equipment have changed over the years. Up-to-date canning instructions from reliable sources (e.g., the U.S. Department of Agriculture or the U.S. Food and Drug Administration) should be followed to ensure food safety. Processed food should be stored properly and heated thoroughly prior to consumption. Because of the possible presence of spores, honey should not be given to infants (≤12 months of age). Injection of illicit drugs should be avoided. All wounds should be meticulously cleaned to eliminate possible contamination with bacterial spores. Clinicians should educate individuals or family members of at-risk individuals, including infants, illegal drug users, and preparers of home-preserved foods.

Acknowledgment

The authors thank Dr. Jeremy Sobel for his valued contributions to the previous version of this chapter.