Botulism

**Botulism** is a rare and potentially fatal illness caused by a toxin produced by the bacterium *Clostridium botulinum*. The disease begins with weakness, blurred vision, feeling tired, and trouble speaking. This may then be followed by weakness of the arms, chest muscles, and legs. Vomiting, swelling of the abdomen, and diarrhea may also o

## Botulism

A 14-year-old with botulism, characterised by weakness of the eye muscles and the drooping eyelids shown in the left image, and dilated and non-moving pupils shown in the right image. This youth was fully conscious.

### Symptoms

Weakness, trouble seeing, feeling tired, trouble speaking

### Differential diagnosis

Myasthenia gravis, Guillain-Barré syndrome, Amyotrophic lateral sclerosis, Lambert Eaton syndrome

### Preventions

Proper food preparation, no honey for children younger than one

### Prognosis

~7.5% risk of death

ccur. The disease does not usually affect consciousness or cause a fever.

Botulism can be spread in several ways. The bacterial spores which cause it are common in both soil and water. They produce the botulinum toxin when exposed to low oxygen levels and certain temperatures. Foodborne botulism happens when food containing the toxin is eaten. Infant botulism happens when the bacteria develops in the intestines and releases the toxin. This typically only occurs in children less than six months old, as protective mechanisms develop after that time. Wound botulism is found most often among those who inject street drugs. In this situation, spores enter a wound, and in the absence of oxygen, release the toxin. It is not passed directly between people. The diagnosis is confirmed by finding the toxin or bacteria in the person in question.

Prevention is primarily by proper food preparation. The bacteria, though not the spores, are destroyed by heating it to more than 85 °C (185 °F) for longer than 5 minutes. Honey can contain the organism, and for this reason, honey should not be fed to children under 12 months. Treatment is with an antitoxin. In those who lose their ability to breathe on their own, mechanical ventilation may be necessary for months. Antibiotics may be used for wound botulism. Death occurs in 5 to 10% of people. Botulism also affects many other animals. The word is from Latin *botulus*, meaning sausage.

## Signs and Symptoms

The muscle weakness of botulism characteristically starts in the muscles supplied by the cranial nerves—a group of twelve nerves that control eye movements, the facial muscles and the muscles controlling chewing and swallowing. Double vision, drooping of both eyelids, loss of facial expression and swallowing problems may therefore occur. In addition to affecting the voluntary muscles, it can also cause disruptions in the autonomic nervous system. This is experienced as a dry mouth and throat (due to decreased production of saliva), postural hypotension (decreased blood pressure on standing, with resultant lightheadedness and risk of blackouts), and eventually constipation (due to decreased forward movement of intestinal contents). Some of the toxins (B and E) also precipitate nausea, vomiting, and difficulty with talking. The weakness then spreads to the arms (starting in the shoulders and proceeding to the forearms) and legs (again from the thighs down to the feet).

Severe botulism leads to reduced movement of the muscles of respiration, and hence problems with gas exchange. This may be experienced as dyspnea (difficulty breathing), but when severe can lead to respiratory failure, due to the buildup of unexhaled carbon dioxide and its resultant depressant effect on the brain. This may lead to respiratory compromise and death if untreated.

Clinicians frequently think of the symptoms of botulism in terms of a classic triad: bulbar palsy and descending paralysis, lack of fever, and clear senses and mental status ("clear sensorium").

### Infant Botulism

Infant botulism (also referred to as floppy baby syndrome) was first recognized in 1976, and is the most common form of botulism in the United States. Infants are susceptible to infant botulism in the first year of life, with more than 90% of cases occurring in infants younger than six months. Infant botulism results from the ingestion of the *C. botulinum* spores, and subsequent colonization of the small intestine. The infant gut may be colonized when the composition of the intestinal microflora (normal flora) is insufficient to competitively inhibit the growth of *C. botulinum* and levels of bile acids (which normally inhibit clostridial growth) are lower than later in life.

The growth of the spores releases botulinum toxin, which is then absorbed into the bloodstream and taken throughout the body, causing paralysis by blocking the release of acetylcholine at the neuromuscular junction. Typical symptoms of infant botulism include constipation, lethargy, weakness, difficulty feeding, and an altered cry, often progressing to a complete descending flaccid paralysis. Although constipation is usually the first symptom of infant botulism, it is commonly overlooked.

Honey is a known dietary reservoir of *C. botulinum* spores and has been linked to infant botulism. For this reason, honey is not recommended for infants less than one year of age. Most cases of infant botulism, however, are thought to be caused by acquiring the spores from the natural environment. *Clostridium botulinum* is a ubiquitous soil-dwelling bacterium. Many infant botulism patients have been demonstrated to live near a construction site or an area of soil disturbance.

Infant botulism has been reported in 49 of 50 US states (all save for Rhode Island), and cases have been recognized in 26 countries on five continents.

### Complications

Infant botulism has no long-term side effects.

Botulism can result in death due to respiratory failure. However, in the past 50 years, the proportion of patients with botulism who die has fallen from about 50% to 7% due to improved supportive care. A patient with severe botulism may require mechanical ventilation (breathing support through a ventilator) as well as intensive medical and nursing care, sometimes for several months. The person may require rehabilitation therapy after leaving the hospital.

## Cause

*Clostridium botulinum* is an anaerobic, Gram-positive, spore-forming rod. Botulinum toxin is one of the most powerful known toxins: about one microgram is lethal to humans when inhaled. It acts by blocking nerve function (neuromuscular blockade) through inhibition of the excitatory neurotransmitter acetylcholine's release from the presynaptic membrane of neuromuscular junctions in the somatic nervous system. This causes paralysis. Advanced botulism can cause respiratory failure by paralysing the muscles of the chest; this can progress to respiratory arrest. Furthermore, acetylcholine release from the presynaptic membranes of muscarinic nerve synapses is blocked. This can lead to a variety of autonomic signs and symptoms described above.

In all cases, illness is caused by the botulinum toxin produced by the bacterium *C. botulinum* in anaerobic conditions and not by the bacterium itself. The pattern of damage occurs because the toxin affects nerves that fire (depolarize) at a higher frequency first.

Mechanisms of entry into the human body for botulinum toxin are described below.

### Colonization of the gut

The most common form in Western countries is infant botulism. This occurs in infants who are colonized with the bacterium in the small intestine during the early stages of their lives. The bacterium then produces the toxin, which is absorbed into the bloodstream. The consumption of honey during the first year of life has been identified as a risk factor for infant botulism; it is a factor in a fifth of all cases. The adult form of infant botulism is termed *adult intestinal toxemia*, and is exceedingly rare.

### Food

Toxin that is produced by the bacterium in containers of food that have been improperly preserved is the most common cause of food-borne botulism. Fish that has been pickled without the salinity or acidity of brine that contains acetic acid and high sodium levels, as well as smoked fish stored at too high a temperature, presents a risk, as does improperly canned food.

Food-borne botulism results from contaminated food in which *C. botulinum* spores have been allowed to germinate in low-oxygen conditions. This typically occurs in improperly prepared home-canned food substances and fermented dishes without adequate salt or acidity. Given that multiple people often consume food from the same source, it is common for more than a single person to be affected simultaneously. Symptoms usually appear 12–36 hours after eating, but can also appear within 6 hours to 10 days.

### Wound

Wound botulism results from the contamination of a wound with the bacteria, which then secrete the toxin into the bloodstream. This has become more common in intravenous drug users since the 1990s, especially people using black tar heroin and those injecting heroin into the skin rather than the veins. Wound botulism accounts for 29% of cases.

### Inhalation

Isolated cases of botulism have been described after inhalation by laboratory workers.

### Injection

Symptoms of botulism may occur away from the injection site of botulinum toxin. This may include loss of strength, blurred vision, change of voice, or trouble breathing which can result in death. Onset can be hours to weeks after an injection. This generally only occurs with inappropriate strengths of botulinum toxin for cosmetic use or due to the larger doses used to treat movement disorders. Following a 2008 review the FDA added these concerns as a boxed warning.

## Mechanism

The toxin is the protein botulinum toxin produced under anaerobic conditions (where there is no oxygen) by the bacterium *Clostridium botulinum*.

*Clostridium botulinum* is a large anaerobic Gram-positive bacillus that forms subterminal endospores.

There are eight serological varieties of the bacterium denoted by the letters A to H. The toxin from all of these acts in the same way and produces similar symptoms: the motor nerve endings are prevented from releasing acetylcholine, causing flaccid paralysis and symptoms of blurred vision, ptosis, nausea, vomiting, diarrhea or constipation, cramps, and respiratory difficulty.

Botulinum toxin is broken into eight neurotoxins (labeled as types A, B, C [C1, C2], D, E, F, and G), which are antigenically and serologically distinct but structurally similar. Human botulism is caused mainly by types A, B, E, and (rarely) F. Types C and D cause toxicity only in other animals.

In October 2013, scientists released news of the discovery of type H, the first new botulism neurotoxin found in forty years. However, further studies showed type H to be a chimeric toxin composed of parts of types F and A (FA).

Some types produce a characteristic putrefactive smell and digest meat (types A and some of B and F); these are said to be proteolytic; type E and some types of B, C, D and F are nonproteolytic and can go undetected because there is no strong odor associated with them.

When the bacteria are under stress, they develop spores, which are inert. Their natural habitats are in the soil, in the silt that comprises the bottom sediment of streams, lakes, and coastal waters and ocean, while some types are natural inhabitants of the intestinal tracts of mammals (e.g., horses, cattle, humans), and are present in their excreta. The spores can survive in their inert form for many years.

Toxin is produced by the bacteria when environmental conditions are favourable for the spores to replicate and grow, but the gene that encodes for the toxin protein is actually carried by a virus or phage that infects the bacteria. Little is known about the natural factors that control phage infection and replication within the bacteria.

The spores require warm temperatures, a protein source, an anaerobic environment, and moisture in order to become active and produce toxin. In the wild, decomposing vegetation and invertebrates combined with warm temperatures can provide ideal conditions for the botulism bacteria to activate and produce toxin that may affect feeding birds and other animals. Spores are not killed by boiling, but botulism is uncommon because special, rarely obtained conditions are necessary for botulinum toxin production from C. botulinum spores, including an anaerobic, low-salt, low-acid, low-sugar environment at ambient temperatures.

Botulinum inhibits the release within the nervous system of acetylcholine, a neurotransmitter, responsible for communication between motor neurons and muscle cells. All forms of botulism lead to paralysis that typically starts with the muscles of the face and then spreads towards the limbs. In severe forms, botulism leads to paralysis of the breathing muscles and causes respiratory failure. In light of this life-threatening complication, all suspected cases of botulism are treated as medical emergencies, and public health officials are usually involved to identify the source and take steps to prevent further cases from occurring.

Botulinum toxin A, C, and E cleave the SNAP-25, ultimately leading to paralysis.

## Prevention

Although the vegetative form of the bacteria is destroyed by boiling, the spore itself is not killed by the temperatures reached with normal sea-level-pressure boiling, leaving it free to grow and again produce the toxin when conditions are right.

A recommended prevention measure for infant botulism is to avoid giving honey to infants less than 12 months of age, as botulinum spores are often present. In older children and adults the normal intestinal bacteria suppress development of *C. botulinum*.

While commercially canned goods are required to undergo a "botulinum cook" in a pressure cooker at 121 °C (250 °F) for 3 minutes,[*citation needed*] and thus rarely cause botulism, there have been notable exceptions. Two were the 1978 Alaskan salmon outbreak and the 2007 Castleberry's Food Company outbreak. Foodborne botulism is the rarest form, accounting for only around 15% of cases (US) and has more frequently resulted from home-canned foods with low acid content, such as carrot juice, asparagus, green beans, beets, and corn. However, outbreaks of botulism have resulted from more unusual sources. In July 2002, fourteen Alaskans ate *muktuk* (whale meat) from a beached whale, and eight of them developed symptoms of botulism, two of them requiring mechanical ventilation.

Other, much rarer sources of infection (about every decade in the US) include garlic or herbs stored covered in oil without acidification, chili peppers, improperly handled baked potatoes wrapped in aluminum foil, tomatoes, and home-canned or fermented fish.

When canning or preserving food at home, attention should be paid to hygiene, pressure, temperature, refrigeration and storage. When making home preserves, only acidic fruit such as apples, pears, stone fruits and berries should be used. Tropical fruit and tomatoes are low in acidity and must have some acidity added before they are canned.

Low-acid foods have pH values higher than 4.6. They include red meats, seafood, poultry, milk, and all fresh vegetables except for most tomatoes. Most mixtures of low-acid and acid foods also have pH values above 4.6 unless their recipes include enough lemon juice, citric acid, or vinegar to make them acidic. Acid foods have a pH of 4.6 or lower. They include fruits, pickles, sauerkraut, jams, jellies, marmalades, and fruit butters.

Although tomatoes usually are considered an acid food, some are now known to have pH values slightly above 4.6. Figs also have pH values slightly above 4.6. Therefore, if they are to be canned as acid foods, these products must be acidified to a pH of 4.6 or lower with lemon juice or citric acid. Properly acidified tomatoes and figs are acid foods and can be safely processed in a boiling-water canner.

Oils infused with fresh garlic or herbs should be acidified and refrigerated. Potatoes which have been baked while wrapped in aluminum foil should be kept hot until served or refrigerated. Because the botulism toxin is destroyed by high temperatures, home-canned foods are best boiled for 10 minutes before eating. Metal cans containing food in which bacteria are growing may bulge outwards due to gas production from bacterial growth or the food inside may be foamy or have a bad odor; cans with any of these signs should be discarded.

Any container of food which has been heat-treated and then assumed to be airtight which shows signs of not being so, e.g., metal cans with pinprick holes from rust or mechanical damage, should be discarded. Contamination of a canned food solely with *C. botulinum* may not cause any visual defects to the container, such as bulging. Only assurance of sufficient thermal processing during production, and absence of a route for subsequent contamination, should be used as indicators of food safety.

The addition of nitrites and nitrates to processed meats such as ham, bacon, and sausages reduces growth and toxin production of *C. botulinum*.

### Vaccine

Vaccines are under development, but they have disadvantages, and in some cases there are concerns that they may revert to dangerous native activity. As of 2017 work to develop a better vaccine was being carried out, but the US FDA had not approved any vaccine against botulism.

## Treatment

Botulism is generally treated with botulism antitoxin and supportive care.

Supportive care for botulism includes monitoring of respiratory function. Respiratory failure due to paralysis may require mechanical ventilation for 2 to 8 weeks, plus intensive medical and nursing care. After this time, paralysis generally improves as new neuromuscular connections are formed.

In some abdominal cases, physicians may try to remove contaminated food still in the digestive tract by inducing vomiting or using enemas. Wounds should be treated, usually surgically, to remove the source of the toxin-producing bacteria.

### Antitoxin

Botulinum antitoxin consists of antibodies that neutralize botulinum toxin in the circulatory system by passive immunization. This prevents additional toxin from binding to the neuromuscular junction, but does not reverse any already inflicted paralysis.

In adults, a trivalent antitoxin containing antibodies raised against botulinum toxin types A, B, and E is used most commonly; however, a heptavalent botulism antitoxin has also been developed and was approved by the U.S. FDA in 2013. In infants, horse-derived antitoxin is sometimes avoided for fear of infants developing serum sickness or lasting hypersensitivity to horse-derived proteins. To avoid this, a human-derived antitoxin has been developed and approved by the U.S. FDA in 2003 for the treatment of infant botulism. This human-derived antitoxin has been shown to be both safe and effective for the treatment of infant botulism. However, the danger of equine-derived antitoxin to infants has not been clearly established, and one study showed the equine-derived antitoxin to be both safe and effective for the treatment of infant botulism.

Trivalent (A,B,E) botulinum antitoxin is derived from equine sources utilizing whole antibodies (Fab and Fc portions). In the United States, this antitoxin is available from the local health department via the CDC. The second antitoxin, heptavalent (A,B,C,D,E,F,G) botulinum antitoxin, is derived from "despeciated" equine IgG antibodies which have had the Fc portion cleaved off leaving the F(ab')2 portions. This less immunogenic antitoxin is effective against all known strains of botulism where not contraindicated.

## Prognosis

The paralysis caused by botulism can persist for two to eight weeks, during which supportive care and ventilation may be necessary to keep the patient alive. Botulism can be fatal in five to ten percent of people who are affected. However, if left untreated, botulism is fatal in 40 to 50 percent of cases.

Infant botulism typically has no long-term side effects but can be complicated by treatment-associated adverse events. The case fatality rate is less than two percent for hospitalized babies.