Etiology

Botulism is the acute, flaccid paralysis caused by the neurotoxin produced by Clostridium botulinum or, infrequently, an equivalent neurotoxin produced by rare strains of Clostridium butyricum and Clostridium baratii. C. botulinum is a gram-positive, spore-forming, obligate anaerobe whose natural habitat worldwide is soil, dust, and marine sediments. The organism is found in a wide variety of fresh and cooked agricultural products. Spores of some C. botulinum strains endure boiling for several hours, enabling the organism to survive efforts at food preservation. In contrast, botulinum toxin is heat labile and easily destroyed by heating at ≥85°C for 5 min. Neurotoxigenic C. butyricum has been isolated from a soybean food and from soils near Lake Weishan in China, the site of food-borne botulism outbreaks associated with this organism. Little is known about the ecology of neurotoxigenic C. baratii.

Botulinum toxin is a simple dichain protein consisting of a 100-kd heavy chain that contains the neuronal attachment sites and a 50-kd light chain that is taken into the cell after binding. Botulinum toxin is the most poisonous substance known, the parenteral human lethal dose being estimated at 10⁻⁶ mg/kg. The toxin blocks neuromuscular transmission and causes death through airway and respiratory muscle paralysis. Seven antigenic toxin types, designated by letters A-G, are distinguished by the inability of neutralizing antibody against 1 toxin type to protect against a different toxin type. Toxin types are further differentiated into subtypes by differences in the nucleotide sequences of their toxin genes. Like the gene for tetanus toxin, the gene for botulinum toxin for some toxin types and subtypes resides on a plasmid.

The 7 toxin types serve as convenient clinical and epidemiologic markers. Toxin types A, B, E, and F are well-established causes of human botulism, whereas types C and D cause illness in other animals. Neurotoxigenic C. butyricum strains produce a type E toxin, whereas neurotoxigenic C. baratii strains produce a type F toxin. Type G has not been established as a cause of either human or animal disease. The phenomenal potency of botulinum toxin occurs because its 7 light chains are zinc-endopeptidases whose substrates are 1 or 2 proteins of the docking complex by which synaptic vesicles fuse with the terminal neuronal cell membrane and release acetylcholine into the synaptic cleft.

Epidemiology

Infant botulism has been reported from all inhabited continents except Africa. Notably, the infant is the only family member who is ill. The most striking epidemiologic feature of infant botulism is its age distribution, in which in 95% of cases the infants are between 3 wk and 6 mo of age, with a broad peak from 2 to 4 mo of age. Cases have been recognized in infants as young as 1.5 days or as old as 382 days at onset. The male : female ratio of hospitalized cases is approximately 1 : 1, and cases have occurred in most racial and ethnic groups.

Infant botulism is an uncommon and often unrecognized illness. In the USA, about 80-100 hospitalized cases are diagnosed annually; more than 2,500 cases were reported from 1976 to 2010. The full clinical spectrum of infant botulism includes mild outpatient cases and fulminant sudden death cases. Approximately 40% of U.S. hospitalized cases have been reported from California. Consistent with the known asymmetric soil distribution of C. botulinum toxin types, most cases west of the Mississippi River have been caused by type A strains, whereas most cases east of the Mississippi River have been caused by type B strains. One case each in New Mexico, Washington, Ohio, California, Iowa, and Colorado has been caused by C. baratii and type F toxin. Four cases in Italy have resulted from C. butyricum and type E toxin. Identified risk factors for the illness include breast-feeding, the ingestion of honey, and a slow intestinal transit time (<1 stool/day). Breast-feeding may provide protection against fulminant sudden death from infant botulism. Under rare circumstances of altered intestinal anatomy, physiology, and microflora, older children and adults may contract infant-type botulism.

Food-borne botulism results from the ingestion of a food in which C. botulinum has multiplied and produced its toxin. Outbreaks in North America have been associated with baked potatoes, sautéed onions, and chopped garlic served in restaurants, revising the traditional view of food-borne botulism as resulting mainly from home-canned foods. Other outbreaks in the USA have occurred from commercial foods sealed in plastic pouches that relied solely on refrigeration to prevent outgrowth of C. botulinum spores. Uncanned foods responsible for food-borne botulism cases include peyote tea, the hazelnut flavoring added to yogurt, sweet cream cheese, sautéed onions in “patty melt” sandwiches, potato salad, and fresh and dried fish. A trend toward a single case per outbreak or of cases manifesting separately in different cities or hospitals portends that physicians cannot rely on the temporal and geographic clustering of cases to suggest the diagnosis.

Most types of preserved foods have been implicated in food-borne botulism, but the usual offenders in the USA are the “low-acid” (pH ≥ 6.0) home-canned foods such as jalapeño peppers, asparagus, olives, and beans. The potential for food-borne botulism exists throughout the world, but outbreaks occur most commonly in the temperate zones rather than the tropics, where preservation of fruits, vegetables, and other foods is less common.

Approximately 5-10 outbreaks and 20-25 cases of food-borne botulism have occurred annually in the USA. Most of the continental U.S. outbreaks resulted from proteolytic type A or type B strains, which produce a strongly putrefactive odor in the food that some people find necessary to verify by tasting. In contrast, in Alaska and Canada, most food-borne outbreaks have resulted from nonproteolytic type E strains in Native American foods, such as fermented salmon eggs and seal flippers, which do not exhibit signs of spoilage. A further hazard of type E strains is their ability to grow at the temperatures maintained by household refrigerators (5°C).

Wound botulism is an exceptionally rare disease, with <400 cases reported worldwide, but it is important to pediatrics because adolescents and children may be affected. Although many cases have occurred in young, physically active males at greatest risk for traumatic injury, wound botulism also occurs with crush injuries in which no break in the skin is evident. In the past 15 yr, wound botulism from injection has become increasingly common in adult heroin abusers in the western USA and in Europe, not always with evident abscess formation or cellulitis.

A single outbreak of inhalational botulism was reported in 1962 in which 3 laboratory workers in Germany were exposed unintentionally to aerosolized botulinum toxin. Some patients in the USA have been hospitalized by accidental overdose of therapeutic or cosmetic botulinum toxin.

Pathogenesis

All forms of botulism produce disease through a final common pathway. Botulinum toxin is carried by the bloodstream to peripheral cholinergic synapses, where it binds irreversibly, blocking acetylcholine release and causing impaired neuromuscular and autonomic transmission. Infant botulism is an infectious disease that results from ingesting the spores of any of the 3 botulinum toxin-producing clostridial strains, with subsequent spore germination, multiplication, and production of botulinum toxin in the large intestine. Food-borne botulism is an intoxication that results when preformed botulinum toxin contained in an improperly preserved or inadequately cooked food is swallowed. Wound botulism results from spore germination and colonization of traumatized tissue by C. botulinum; it is the analog of tetanus. Inhalational botulism occurs when aerosolized botulinum toxin is inhaled. A bioterrorist attack could result in large or small outbreaks of inhalational or food-borne botulism (Chapter 704).

Botulinum toxin is not a cytotoxin and does not causes overt macroscopic or microscopic pathology. Secondary pathologic changes (pneumonia, petechiae on intrathoracic organs) may be found at autopsy. No diagnostic technique is available to identify botulinum toxin bound at the neuromuscular junction. The healing process in botulism consists of sprouting of new terminal unmyelinated motor neurons. Movement resumes when these new twigs locate noncontracting muscle fibers and reinnervate them by inducing formation of a new motor end plate. In experimental animals, this process takes about 4 wk.

Clinical Manifestations

Botulinum toxin is distributed hematogenously. Because relative blood flow and density of innervation are greatest in the bulbar musculature, all forms of botulism manifest neurologically as a symmetric, descending, flaccid paralysis beginning with the cranial nerve musculature. It is not possible to have botulism without having multiple bulbar palsies, yet in infants, such symptoms as poor feeding, weak suck, feeble cry, drooling, and even obstructive apnea are often not recognized as bulbar in origin (Fig. 202-1). Patients with evolving illness may already have generalized weakness and hypotonia in addition to bulbar palsies when first examined. In contrast to botulism caused by C. botulinum, a majority of the rare cases caused by intestinal colonization with C. butyricum are associated with a Meckel diverticulum accompanying abdominal distention, often leading to misdiagnosis as an acute abdomen. The also rare C. baratii type F infant botulism cases have been characterized by very young age at onset, rapidity of onset, and greater severity of paralysis.

Figure 202-1

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